Note: Descriptions are shown in the official language in which they were submitted.
Z~ 39
Title: PHARMACEUTICALSELECTIVE TISSUE NECROSIS
FI~L~ OF T~E ~
The present invention relates to pharmaceuticals
and apparatus to implement the Mo~sbauer effect for
diagnostic and therapeutic purposes.
,. ~C=~
~n the treatment of tumors by ionizing
r~d~ation, typically X-rDys or ga~ma rays are u~ed.
Tha ideal i~ radiation therapy of malignant dlsease
i~ achieved when the tumor i~ co~pletely eradicated,
a~d the surrounding normal ti88Ue, in the treated
volume, shows little or no evidence of structural or
functional i~ury. The important factor in
success~ul treatment i~ the difference in
radio~en~itivity of neopla~tic and normal coll~. All
ti~ueJ, normal and neopla~tic, are affected by
ra~iation so that radio~en~itiyit~ i~ a relative
term. Th~ basic con~ideration of radiatlon therapy
iJ that cell~ that are a~tively proliferating or that
cellJ whlch ar~ of a prlmitive type aro more
~on~itive than normal tiYgu~ 80 that there i~ u~ually
a con~iderable marqin between do~e~ that are damaging
to neoplastic and to normal cells. If this i~ the
caae, then a multifraction ~08e schedule decrea~es
the size of the tumor over time while pormitting time
between doses for normal tissue to recover. A
constant fraction of tumor cells are killed with each
treatment, and theoretically the tumor can be
completely eliminated with a sufficient number of
treatments. However, normal tissue has a memory of
its accumulated radiation dose such that a threshold
to the total dose acquired over the patiPnt's history
is eventually reachPd. E~ceeding this threshold
results in unacceptable side effects. Thus, the
tumor volume must be reduced sufficiently before the
- threshold is reached or the cancer is incurable by
this modality of therapy.
SUMMARY QF T~ INVFE~Q~
15The present in~ention is pharmaceuticals,
- apparatus, and a process which provides diagnosis,
therapy and other biological effects by use of highly
selective absorption of rad$ation called the
Mossbauer effect. Mossbauer absorption which is
e~ploited for diagnosis and therapy by the present
invention is completely analogous to optical
absorption. For purposes of the present application,
! Mossbauer resonance is synonymously defined as an
energy and a frequency which are interchangeable by
the relationship:
c ~ ~ h~
For optical absorption, the ultimate source of
radiation consists of e~cited atoms or molecules
which decay to the ground state. The radiation,
after being suitably monochromatized by a prism or
diffraction grating, is incident upon the sample, and
the intensity of the beam which is transmitted
through the sample (absorber) varies as a function of
3~3
-- 3 --
th~ frequency as the photons of energy equivalent to
electronic, vibrational, rotational, and
t~anslational transitions are absorbed. In Mossbauer
absorption, the source comprises e~cited nuclei in
S appropriate highly bondinq surroundings. The nuclei,
in dacayinq to their ground stats, emit gamma
radiation that i5 highly monochromat$c. In fact, the
gamma ray line can be so narrow that i~s fre~uency
may ba shifted signiicantly b~ incorporating the
~ource or ab~orber in a mass driver oscillating at
moderate velocities to produce a Doppler ef~ect. The
velocity of the mass driver which provides a Doppler
shift to the gamma ray photons functions analogously
to the dispersion device in optical absorption. By
varying the driving velocity, a re~onance system can
b~ driven by the emitted gamma photons with regard to
the nuclear energy transition~ of the sample
~absorber).
A~ p~rt of the present invention, useful
ayplication of th~ Mossbauer efect in livinq tissua
i~ provided by an administered pharmaceutical
containing a Mossbauer isotope as the absorber. The
pharmaceutical i~ re~onantly e~cited by the gamma
photon~ provided by this apparatus where the gamma
ray energy, polarization and propagation direction
are ro~onant w1th the nuclear transitions of the
i~otope i~ the target ti~aue, from which the
~urroundlnq nontarget ti88ua d~ffers significantly in
r-~onance conditions to achieve an enhanced
therape~ttc or dlagnostic ~u~ction and minimum
effect~ in th~ nontarqet tissue.
A~ a further aspect of the present invention the
r~sonant (Mossbauer) absorption o~ gamma ray~ by
nuclei of the administered i30tope~ at the target
ti~ue, provides a specific, lethal release of energy
Z6~ t..~
-- 4
':
to a susceptible biological taryet such as the DN~ of
- the target tissue as part o a therapeutic process.
Alternatively, the present invention pro~ides
diagrams by monitoring the release o nonlethal
energy, as described in detail, below. An acronym
for Mossbauer Isotopic Resonant Absorption of Gamma
Emission, hereafter, MIRAGE, is created, and ths
corre~ponding therapy and pharmaeeuticals are
diselosed a~ MI~AG~ th~rapy and MIRAGE
pharmaceuticals.
~he MIRAGE pharmaceuticals contain ~ossbauer
absorber isotopes and bind to a target tissue to
become immobilized, permitting Mossbauer nuclear
resonant absorption of q~mma radiation in the
vicinity of the target tissue. The eYcitation is by
a radiation source, the apparatus of the invention,
- at the correspond~ng re~onant Mossbauer absorption
frequency of selected tissue haYing received the
administered pharmaceutical where e~citation effects
nuclear transition~ to c~use selective energy
absorption in the selected target tissue. For
d~agnostic purposes, dQ-escitation fluorescence of
the i80tope i~ monitored with gamma ray scanning
equipment. For therapeutic purposes, tho energy is
converted into particle radiation by the Mossbauer
isotope at the t~rget tis~ue b~ intornal conversion
followed by an Auqer cascade which results in damage
to a susceptible biological target such as radiolysis
o~ D~A result~ng in lethal double strand breaks in
tho D~A molecules of tho target tissue.
- Tis~ue solect~vity i8 achieved by causing the
Mo3sbauer effect to occur to a greater e~tent in the
solected target tissue than tho nontarget tissue.
On~ a~pect of tho pre~ent inYentiOn providing
solectivity is by administering pharmaceutical~ which
X ~ ~.JO~
_ 5 _
are salectively taken up by the s~lected tissue.
: Alternate embodiments of the present invention
selectively control Mossbauer resonant absorption by
control of the condition~ for resonance o~ gamma ray
eneryy, polarization, and propagation direction,
wherein pharmaceuticals when in the vicinity of
selected vorsus nonselected tissue, hava a
differential of one or mOrQ such conditions. Such
conditions are made different by magnetic fields or
ultrasonic power which are applied, effecting an
absorption differential for solected versus
nonselected tissue. Mossbauer absorption at the
tarqet tissue is provided by shi~tinq the source
~requency to conform to that of the MIRABE isotope in
the vicinity of the target tissue. Alternately the
absorption characteristic~ of the MIRAGE isotope i~
controlled to match the imparted radiation at the
~ite o~ the target tissue.
Apparatus provid~ng the selectively ~hited
ra~iation comprisea a Mos~bauer ~ource supported by a
ma~s drive or ultrasonic tran~ducer drivo which can
suitably ~tune~ the emitted radiation to the proper
Mossbauer a~sorption frequency by imparting a Doppler
frequency shi~t or by shifting the energy of emis~ion
sidQ band~, re~pectively. In ad~ition, the apparatus
includes moans to polar$ze the emission and possesses
m~an~ to produce e~ternal magnetic flelds and an
ultrason$c b~m to effect solectivo ab~orption by
changing tho qamma ray energy and~or polarization and
propagation dlrection conditions to achievo resonance
in tho absorber pharmaceutical solect~vely.
In addition, the pre~ent inventlon include~
apparatus to separately and controllab~y polarize
both tho emis~ion radiation an~ tho ab~orber
pharmaceutical at the target tis~ue to achieve the
03~3
-- 6 --
~.
desired controlled absorption. Alternate embodiments
of the apparatu~ according to the present invention
provide selectively controlled esternal magnetic
fields at the target tissue to effect selective
absorption by changing the gamma ray energy and/or
polarization and propa~at~on d~rection conditions to
achieve resonance in the ~RAG~ absorber
pharmaceutical. The Apparatus, Sy8tems, Compounds,
Methods, and specifications of u~e are described in
detail below.
3RIEF DEscRlpTIo~ OF T~DRA~L~
These and other features of the present
in~ention will be better understood by reading the
following detailed description taken together with
the drawing, wherein:
Fig. 1 i~ one em~odim~nt o the syste~ apparatus
of the present in~ention;
Fiq. 2 is an alternate embodiment of the system
apparatus of the pre~ent in~ention;
Fig. 3 i~ an alternate eubodiment of a portion
of the system of Figs. 1 or 2, showing the position
of surface coils;
Fig. ~A is a plot o the field produced by the
coils disposad in Fig. 3;
F~g~ 4 is an alternate ~mbodiment of the
dispositio~ of Helmholtz and a surface coil;
Fig. 4A is a plot of tho field produced by the
coi 18 of Fig. 4;
Flgs. S and 5A are drawings of a surface coil;
Flg. 5B i3 a plot of the field produced by the
coil of Fiq. 5:
Fig. 6 i~ an isometric view of an alternate
embodiment of an array of coils ~or u~e in the system
apparatus of Figs. l and 2;
. _ 7 --
Fig. 7 is an isometric drawing o~ a system
according to the present invention showing ultrasound
modulation of the ganma ray source and the Mossbauer
atom at the target area;
Flgs. 8 and 9 are graphical plots of data
relat~d to radiation therapy;
- Figs. lOA, B and C are diagrammatic
representations of the MIRA OE pharmaceutical 12~29/w;
Flg. 11 is the decay schema of 5~Co;
Fig. 12 is the decay sche~e of L~SA;
Fig. 13 is the decay scheme of l2~mSm;
Fig. 1~ is a decay scheme of l2~I;
F~g. 15A is the energy level scheme and 15B is
the resultant spectrum for maqnstic hyperfine
splitting of an Ig = 1~2 - Ia - 3/2 transition,
wherein the relative splittings are scaled in accord
with the magnetic moments of ~S~;~g=
1.04~ and ~e+0.67~N, and the line
intensit~ ratio~ of ~:2:1:1:2:3 are appropriate to a
polycry~talline absorber;
Flgs. 16A and B are drawing~ showing relative
l~ne inten~ities of a magnetic hyperÇine splitting
and a quadrapole splitting of a 3~2~1~2 transition
in an oriented absorber with a unique principle a~is
system; and
Figs. 17A and ~ are the spectra from a single
crystal of ~-Fe2O3 cut p~rallel to the basal
plane with the gamma ray direction along 111, wherein
Flg. 17A is the spectra of Fig. 17 at 80K and
Fig. 17~ i~ the spectra of Flg. 17 at 300R.
~,.
~Q~)~()39
The present invention includes the process of
producing pharmaceuticals having desired Mossbauer
nuclear parameters such that they possess physical
and chemical properties which permit the Mossbauer
phenomenon to be selectively e~fected in the target
tissue. The application includ~s administering the
pharmaceuticals and producing gamma radiation of the
proper polarization, propagation direction, and
energy with the radiation source to cause selective
resonant absorption in the target tissue. ~he
present invention also includes producing magnetic
fields or an ultrasonic beam both of selected
strength and direction with the apparatus of the
radiation source to effect sclecti~e gamma ray
absorption in the target tissue via the Mossbauer
efect.
~ he pharmaceuticals of the presen~ invention and
the proce~s of producing the pharmaceuticals is
discu3sed first, which is followed by the apparatu~
used in combination with selected pharmaceuticals to
effect th~ Mossbauer absorption in a biological
target as a proce~ of the in~ention to provide a
therapeutic or diaqnostic function. The latter,
apparatu~, provides a monochromatic source of gamma
ray~ ha~ing an e~ission frequency or energy at or
noar the (or substantially monochromatic over the
rs~ge of frequencie~ where ~ossbauer absorption may
occur in irradiated tissue) nuclear transitions of
on~ or more Mossbauer atoms incor~orated in the
pharmaceuticals. Subsequently dl~cussed are the
features of the present invention wherein the energy
which e~ites the nuclear transition is released as
light which can ~e recorded for diagnostic purposes,
or the energy is converted into charged particles or
~Qg~5~13~3
-- 9 --
reactiYe species which irreversible damage a
biological target to effect a therapeutic function.
Selectivity in treatment or diagnosis is
obtained by causing the gamma ray absorption to occur
with the Mossbauer absorber atoms of the
pharmaceuticals in the tarqet tissue to a sreater
estent than i~ the nontarget tissue due to
differential uptake of the pharmaceutical or a
differential in the conditions of the source gamma
rays needed to achieYe resonant absorption by the
absorbers including a difference in energy and~or a
diference in polarization and gamma ray propaqation
direction relative to the direction of the magnetic
or quadrapole moments of the absorber ~ossbauer atoms
in the pharmaceuticals. Dlfferential uptake involves
physical chemical and biological properties of the
pharmaceuticals which in~luence its uptake by cells.
The differential resonance conditions of gamma
r~y energy and~or polarization and propagat~on
dlrection are pro~ided by di~ferent chemical and~or
phy~ical interactions of the ~ossbauer atoms o the
pharmaceuticals with the en~ironment i~ which they
are present in target versu~ nontarget tissue.
Furthermore magnetic fields or an ultra~onic beam
are selectively applied to the target area in such a
fa~h$on to produce a differential of these resonance
condition~ at different locations. rherefore
treatmsnt i~ carried out by irradiating the selected
tl~ue with gamma rad$ation o the proper energy and
polarization and gsmma ray propaqation direction to
match the conditions for re30nant ab~orption by the
Mossbauer absorber isotope atoms of the
pharmaceutical molecules present in the tarqet
selected tissue.
o~
-- 10 --
Implementation of the process for making M~RA~E
pharmaceuticals involves selecting an atom responsive
to the Mossbauer effect at a conv~nient frequency,
salecting the structure of the molecule to which the
Mossbauer respon~ive atom (Mossbauer Atom) is
attached, selecting the type o~ bond to form between
the ~ossbauer atom and ths r~mainder of the
pharmaceutical and the position at which the
Mossbauer atom is attached. Mo~sbauer nuclear
parameters (i.e., Table 8, include~ absorption line
width, recoil energy, nuclear magnetic moment,
internal conversion coefficient, X-ray energy,
magnetic quantum numbers of the ground and e~cited
state~ are used in calculations as demonstrated in
the Theoretical Section, below, to perform the
followinq steps in the design of the pharmaceutical:
1. A Moss~auer atom i~ selected such that it
posse~ses chemical reactivity to form a bond of the
nature described b~low under 3, a larqe cross-s~ction
for ab~orption of resonant gumma radiation with
de-e~citation primarily by p~rticle production or
fluorescence for the purposes of therapy and
diagno~tic imaginq, respectively, a low recoil energy
which is smaller than the vibrational energy o~ the
bond between the Mossbauer ato~ and the remainder of
the pharmaceutical molecule, a large nuclear moment
which interacts with an imposed maqnetic ield to
llft the de~eneracy of e~isting magnetic sublevels to
a siynificant estent that spatial discrlmination with
rogard to the occurrence of t~e Mos~bauer effect can
b~ re~lized by changing the m~gnetic field direc~ton
and magnitude to change the resonance conditions of
g~mma ray energy and~or polar~zation and propagation
direction, and a small absorption~ line width so that
aforementioned di3crimination can be realized over
~Q5~
11 --
small spatial dimensions, and so that an ultrasonic
maans of discrimination of shiftinq the Mossbauer
absorption energy as described in the Theoretical
Section can be realized with low M~z frequencies.
2. A molecular structure to which the Mossbauer
atom is to be bound is salected such that it
possesses th~ ability to also be bound to the
selected biological target to immobilize the
~ossbauer atom to pre~ent degradation of the
Mossbauer effect by escitation of translational modes
of the pharmaceutical molecule, that i~ certain cases
is se}ectively taken up by the selected tissue, and
that in certain cases interacts with the environment
of the selected tissue different$ally relative to
nonselected tissue to cause different conditions to
achieve resonance between these tissues.
3. ~he bond between the Mossbauer atom and the
remainder of the pharmaceutical molecule i~ selec~ed
such that it po3sesses vibrational modes which are
not escited by the recoil energy of the absorbed
gamma ray~ thus, the Mos~bauer efect i~ not degraded
by this mechanism.
4. The bonding position of the Mossbauer atom or
functionality to the remainder of the pharmaceutical
molecule has no effect on the binding affinity of the
latter for the biological target.
The photon flu~ nece~ary for effective
troatment is calculated where v~riable~ for each of
th~ afore mentioned de~ign parameter~ are included in
ths calculation, and the strength and direction of
imposed magnetic fielas to obtain selectivity are
alæo calculated. 30tn types of calculations are
demonstrated in the Theoretical Sect~on.
The pharmaceutical possesses physical and/or
chemical properties which permits it to bind
.
o~
- 12 -
sufficiently tiqhtly to a massive bioloqical tarqet
so that the effective mass of the Mossbauer atom
which is incorporated in the pharmaceutical is the
mass of ths biological targe~. Ths e~fective mass is
S sufficient to prevent escitation of translational
modes of the Mossbauer atom by ths recoil energy of
the absorbed gamma ray. Furthermore, the chemical
bond between the Mossbauer atom and the remainder of
ths pharmaceutical has a bond enerqy that precludes
L0 e~citation of vibrational mode3 of the bond by the
recoil energy of the ab~orbed ~amma ray. The
pharmaceutical contains at le~st one Mossbauer atom
which has a large cross-6ection for absorption and
the atom de-escites primarily by fluorescence in the
case of imaging pharmaceuticals and the atom converts
ths e~citation energy primarily into charged
particles and reactive species i~ the case of
therapeutic pharmaceuticals. Also, the
pharmaceutical possess physical and chemical
propertie~ so that it is selectlvely taken up b~
selected cells, or it possesse~ Mossbauer nuclear
parameters which permit the nucleus of the Mossbauer
atom to interact with an imposGd magnetic field with
a resultant change in the resonance conditions of
gamma ray ener~y and~or polarization and propagation
d~rection to a sufficient degree that selectivity of
target versus nontarqet tissue3 can be achieved by
this interaction.
A further feature of the pre~ent invention i~
the use of s~lected phar~aceuticJls and apparatus
do~cribed herein in comblnation to apply the
Mossbauer effect to treat selected tissues.
Treatment include~ providinq selective uptake o~ a
cpecific pharmaceutlcal b~ the tarqet tlssue, and
irradiation of the tarqet tissue with selected enersy
:
.,
:
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~:0~ ,'9
- 13 -
(frequency) radiation produced by the apparatus of
one embodiment. The apparatus may also apply a
magne~ic field to cause the resonance conditions of
gamma ray energy and polarization and propagation
direction necessary to produce nuclear transitions in
the absorber, to match these conditions o~ gamma rays
produced hy the source for the case of a stationary
source (non-Doppler shifted, nonultrasonically
driven~. And, where the applied pharmaceutical is
present in nonselected tassue, selectivity in
treatment is provided by the imposition of Çields by
the apparatus to ~orce differenti21 resonance
conditiuns of gamma ray energy and~or polarization
and gamma ray propagation direction for resonant
- 15 nuclear absorption by the Mossbauer absorber atoms of
the target tissue to provide treatment to a t$ssue
selected area or volume.
Magnetic fields are applied to the body where
tha field magnitude and direction change rapidly as a
functio~ of position in the space permeated by the
field. The gamma rays of the source are made to
match the gamma ray energy, polarization and
propagation direction conditions for resonant nuclear
absorption by the Mossbauer atoms of the
pharmaceuticals present in the t~rget tissue.
Selectivit~ of treatment in this case is achieved
b~cau8e the conditions for nuclear resonant
abaorption in nonselected tissue through whlch the
gamma rays travel to the s~lected t~ssue are
d~ferent from those o~ the selected ti~sue.
Th~ radiation of energy in re~onance with the
selected i~otope and of proper polarization and
propagation d~rection is produced by the apparatus
which includes a selectable energy source such as a
synchrotron source or a Mossbauer source which
2~ 03~3
- 14 -
corresponds to the selected isotope (corresponding
sources to selected absorber isotopes to ~e
incorporated into pharmaceuticals appear in
Table 7). The Mossbauer source is incorporated into
a mass drive which can suitably tune the emitted
radiation to the proper Mossbauer absorption
frequency by imparting a Doppler s~i~t, or the
Mossbauer sour~e can be adhered to a ultrasonic drive
which creates emission side bands of energy which is
selectable according to the ultrasonic driving
frequency as described in the Theoretical Saction, or
magnetic fields may be applied to the target tissue
such that the energy conditions for resonant
absorption by the selected absorber isotope o~ the
pharmaceutical are forced to match those o~ the
stationary source. In addition, the apparatus
includes a polarizing element, to polarize the
emission. Polarized gamma rays are obtained by three
methods: magnetized ferromagnetic sources,
quadrapole split sources, or f~lter techniques. In
addition, the apparatus possessQs means to produce
e~ternal magnetic ~ields and ultrasonic beams to
changa the gamma ray energy and~or polarization and
propagation direction conditions to achieve resonant
absorption in the absorber atoms of the
pharmaceuticals to impart tlssue ~electivity
accordinq to the present invention. Magnetic fields
and ultra30nic beams are produced by powerful surface
coils such a~ those used in magnetic resonance
imaging and pie~o-electric transducers and transducer
arrays such a~ those used in ultrasonic imaging,
respec~ively. Such ~agnetic field producinq means
and ultrasonic beam producing means are described
below in the Apparatus Section.
- 15 -
Tha process o~ providing selectivity by
imparting magnetic fields with the apparatus involves
providing a magnetic field in space which contains
the selected tissue~ Thus, spatial discrimination
with regard to the occu~rence of the ~ossbauer effect
can be realized by selectively changing the field
direction and strength to change the resonance
conditions of gamma ray enQrgy and~or polarization
and propaqation direction in a specified area or
volume Or tissue. The Mossbauer atoms of the
pharmaceuticals possess magnetic moments which
interact with the imposed magnetic fialds to cause
the effects of creation of nondegenerate magnetic
- sublevels and alignment of the nuclear moments along
the direction of the field lines with a concomitant
aliqnment of the tissue resonance. The lifting of
the magnetic sublevel degeneracy changes the energy
for resonant absorption by the Mossbauer atoms and is
a function of the imposed magnetic f~eld strength and
the magnetic ~oment of the particular absorber
atoms. Magnet~c fields which change rapidly in
strength and time (or pulsed fields) are used to
create a selective situation where the energy ~or
resonance change~ rapidly alony the field gradient;
thus, the energy of the source can be conformed to
: the enerqy for resonant absorption by the absorbers
at the selected tissue site such that the resonant
condition is satisfied only ovsr the volume of the
solected site. The alignment effect results in a
dcpendQncy on the angle botween the alignment
direction o th~ nuclear moment~ of the absorber
atoms and the propagation direction and polarization
propertie~ of gamma rays for resonant absorption by
the absorbers to occur. Fields which change rapidly
in vector direction in space and time (for pulsed
~ .
,
': '
:f
- 16 -
fields) are used to create a rapidly chanying spatial
distribution of populations of atoms with the
magnetic moments aligned in different directions.
Thus, a magnetic field is provided wherein thP
magnetic moments of all of the Mossbauer atoms in the
nonselected tissue through which the gamma ray
tra~els are in a nonresonant orientation, and the
Mossbauer atoms in the selected tissue are in a
resonant orientation. Thus, selectivity is achieved
by this alignment effect according to the
; txansparency of the nonselected tissue to the gamma
ray~ and absorption by the selected tissue.
The process of treatment involves using the
pharmaceuticals and apparatus in combination to cause
the Mossbauer effect to occur to a greater e~tent in
the selected tissue than in the nonselected tissue.
The tissue is irradiated with gamma radiation of
energy and polarization and propagation direction
re~onant with the nuclear transition~ of th~ selected
tissue. Selectivity is achie~ed because ths druq is
uptaken by the selected tissue to a greater e2tent
than the interposed nonselected tissue through which
the gamma ray propagates. Or, a magnetic field of
rapidly divergent strength and direction is applied,
or an ultrasonic beam is applied. For the ultrasonic
ca8e~ tha proce~s of effectinq selectivity by causing
a~ ultrasonic beam to intersect the administered
gamma ray baam at ~he selected tissue site involves
producing a component of ultrasonic motion of the
Mo~sbauer absorber nuclei in the selected tissue in
the direction of the g~mma ray b~am to produce
- absorption side bands o~ energy different from those
of nonselected tissue through which the gamma rays
reYonant with a selected side band propagate. The
production of absorption side bands by driving at
- 17 -
ultrasonic frequencies is described in the
Theoretical Section. In ths magnetic case, the
phenomenon of the maqnetic field strength dependence
of the lifting of the deqeneracy of magnetic
sublevels of n~clear transitions and nuclear magnetic
moment alignment with the magnetic field li~es and
the concomitant dependenc~ for resonant ab~orption on
the angle between the nuclear magnetic moment and the
gamma ray propagation direction and polarization of
the gamma ray can be used to force a matching set of
conditions by the apparatus between the source and
the Mossbauer absorber atoms in the pharmaceuticals
in the selected tissue. The parameters which are
chansed to achieve this result are the energy of the
source gamma rays (e.g. by changing the velocity of
the mass drive), the polarization of the source gamma
rays (e.g. by changing the direction of the source
polarization maqnetic field in the case of a
ferromaqnetic source), the magnetic field strength
gradient (e.g. by chanqing the current in the surface
coil~ which give rise to tbe field and the
distribution of the coils about the treatment
volume), and the propagation direction of the gamma
ray by changing the relative position of the source
of magnetic fields and the source of gamma rays.
If the set of parameters which produce resonance
selectively in the selected tis~ue are known (for
esample from calculations such as those demonstrated
in the Theoretical S~ction or from prior
e~periment~, than the therapy is carried out in an
open loop fa~hion. For e~ample, for the case where
the dr'ug i~ selectively uptaken b~ the selected
tissue or ha~ a unique energy for ab~orption in the
selected tissue, the resonance energy of the source
and ab~orber are forced to match each other by
,,~ ,,,
.,
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2~5(~3
- 18 -
changing the energy of the source to match the energy
of the nuclear transitions of the absorbers of the
pharmaceutical, or the energy of the transitions of
the absorber are changed to matoh that of the
: 5 source. In the former case, the velocity of the mass
drive or the frequency of the ultrasonic transducer
can be adjusted, and in the latter ca~e, magnetic
fields can be used to change the energy of the
absorber nuclear transitions. Selectivity can be
achieved where the drug is distributed in nonselected
tissue by use of a magnetic field of strong field
gradient so that the energy of resonance is only met
in a small spatial reqion. 5uch a maqnetic field
could be applied, and the energy of the source
adjusted to match that required for resonance in the
selected tissue. This mode of achieving selectivity
could also be used in conjunction with a polarization
mode where the Mossbauer nuclei of the
pharmaceuticals of the selected tissue are aligned
with an imposed ~agnetic field in a resonant
direction with r~spect to the gamma ray propagation
direction and polarization, and the interposed tissue
is made transparent by orienting the nuclei in a
nonresonent direction. An additional mode of
achie~inq selectivity is to impose a narrow
ultrasonic beam which intersects the administered
gamma ray beam to induce a component of ultrasonic
~otion o~ the Mossbauer absorber nuclei at the
selected tis~ue site to create ab~orption side bands
of unique energy equal to the energy of the
a~ministered gamma rays as described in the Apparatus
and Theoretical Sections.
If the parameters to ach~eve reYonance between
the apparatus and absorbers are unknown, then the
afore mentioned modes o treatment are carried out in
.
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~ ~0~5~39
-- 19 --
a closed loop fashion using gamma ray fluorescence.
All Mossbauer nuclei undergo fluorescent emi~sion to
a certain estent after resonantly absorbing gamma
rays. This phenomenon is used to detect where
resonance is achieved. Fluorescence occurs at
continuum of angles, and a bank of detector~
surrounding the treatment volume is used to detect
the source o fluorescence, as described below.
Thus, the position of the source of fluorescence is
used in a feedback loop which feeds into a control
system which changes the magnetic fiald strength and
direction; ultrasonic beam frequency, direction and
power; and gamma ray energy, polarization, and
- propagation direction until the source of
fluorescence is the selected tissue. Treatment is
then carried out to the level of an absorbed dose
which is known from calculation or past e~perience.
A representative calculation of an effective photon
~lus for treatment to achieve n~crosis and the
associated dose appears in the Theoretical Section as
does the theory of achievinq salectivity by the modes
mentioned. (Implicit is that the process for
diagnosis i5 the same as that ~or treatment with
reqards to escitation. Detection i~ with gamma ray
scanning equipment which can be obtained by
modification of esisting radionuclide scanning
equipment by one skilled in the art.)
2~ 0~9
- 20 -
A. Synth~sis o~ 12/29~w
T~e MIRAGE drug, 1 V29/w, was synthesized ~y
forming a coordinate bond of s~F~ with Bleomyc~n
(see Fig. 10 ~or the structure).
12~12~w was prepared as follows:
Iron 57 metal was obtained from New England
Nuclear DuPont and dissolved in concentrated HCl.
The acidic solution of iron was neutralized with
sodium hydroxide. 12~29/w was prepared by mi2ing a
1:2 molar ratio of a neutral aqueous solution of
Bleno~ane and the neutralized solution of ~JFe. A
stable yellow solution was obtained as the product.
B. C~ll Cu~ty~e Testi~o Of M~AGE_~x~tm~
. ~9~
The human colon and breast cancer cell line~,
HT29 and MCF7, r~spectlvely, were obtained ~rom
Cambridqe Research Lab Inc., and were negat~ve for
mycoplasma or bacterial contaminatio~ where these
tests were performed by Kundsin Lab Inc. A bacterial
and mycoplasma-free McCoy cell line was obtained from
~undsin Lab Inc., which the Kundsin Lab tasted or
these organisms. The human breast and lung cancer
cell lines, HT~26 and A549, respectively, were
obtained from the American Type Culture Collection.
The cells were grown in growth mqdia, Dubecco's
modif1ed Eagles medium with 10~ fotal bovine serum,
50ug~ml streptomycin; lOOug~ml vancomycin, and 2nM
qlutamine. The cells were grown in T25 flasks until
a monolayer was obtained. The monolayer o~ each
flask was washed twice with iron-freo growth media
and the cells were incubated with iron-free media to
.~,. . .
: . .
`
' '
L
2~
- 21 -
which the drug 12~29/w was added. The control
e~periments were no drug and drug for the same
e~posure time and concentration. For the MIRAGE
treatment esperiment, the cell ~onolaye was
incubated in iron free qrowth msdia containing
12~29/w and was irradiated with the 14.~ Ke~ gamma
ray emitted from a New England Nuclear DuPont Co
` Mossbauer source with a rhodium matris where tha
source was driven at a v~locity of +1i5mm~sec by an
Austin Science R4 linear motor controlled by an
Austin Scie~ce S-700 dri~e module where the constant
velocity mode was 85% of the duty cycle. Ater the
time of the esperiment had lapsed, the drug was
removed by washinq the monolayer twice with iron free
growth media and once with phosphate huffered
saline. The cells were trypsinized with 5% trypsin
EDTA and a counted number of cells from each
esperiment was passed into a new T25 flask containing
growth media where counting W~5 p~rformed using
methylene blue stain and a hemocytometer.
The cells were grown as a monolayer for a period
of time after which they were trrpsinized and counted
a second time using methylene blue stain and a
hemocytometer. The percentage increase in cell
number between counts was normalized to that of the
control.
,' ~Efi~
The effects of lm rad le~els of Mossbauer
radiation absorbed during M~RAGE treatmQnt of the
cancer cell lines MCF7, McCoy, HT29, HTB26, and A549
w ing the MIRAGE drug 12~19/w appear in Tables 1-5,
ru~puctivuly.
, '`
~0~0~9
-- 22 --
~` _ 5 C ~ ~o
~ ~ 5 c~ h
~ ~ ~ o
-- 23 --
.: ~
I.L ~ ~_
o
,w
W W W
o
:
:
-- 2 ~ --
e E ~ ~ ~ ~!i;e
o 7 o~ o oO o o
~ ~ 2 9 ~
~ e~
0~3
~ ~ _9 ~ ; _ ~
j U = ~ _ _ ~ o
31 , s ~ o~
,~
`:
'39
o
2~
- 27 -
e~s~x
A s~atistically significant effect was observed
with mrad levels of radiation. PreYious studies
indicate that at least 500 rads of conventional
X-rays or gamma rays is necessary to register a
similar effect. 500 rads is 5s10~ times the level
of radiation used in these MI~AGE treatment
esperiments. Furthermore, lmrad of radiation is far
below levels which are tosic and can be compared to
200mrad which is the yearly background dose.
Furthermore, the MIRAGE pharmaceutical need not be
tosic via chemical or biological re~ctivity, and
pharmaceutical and radiation nonto~icity has
implications of nonto~ic human ~herapy for the
elimination of a pathological cell population.
Previous esperiments demonstrated that the most
potent killing effect in cells by radiation is from
secondary particles produced by i~ternal conversion
of gamma ray energy followed by an Auger ca~cade
which results in the radiolysis of the cell's genetic
; material. The present e~periments indicate that it
is possible to effect this eradication mechanism with
nonto~ic lavels of radiation which are SiY orders of
magnitude less than that of conventional radiation
therapy where the Mossbauer effect was e~ploited for
treatment. The ability to control the occurrence o~
; the Mossbauer effect by the manipulation of the
re~onance conditions is the basis for selective cell
eradication therapy in animals including humans.
STRU~U}OE~oN
One group of MIRAGE drugs i8 formed by
derivatizing the DNA binding molecule~ of Table 6
with Mo~sbauer absorber isotope~ of Table 7 where
derivatizing constitutes the formation of a bond
6~39
- 28 -
between one or more Mossbauer atoms or a
functionality to which one or more Mossbauer atoms is
bound and a DNA binding functionality. ~he MIRAGE
compounds retain the DN~ binding property of the DN~
binding molecule, and contain at least one Mossbauer
atom bound in a ashion to permit the Mossbauer
phenomenon to occur.
For e~ample. the phenyl group of ethidium
bromide (see Table 6 for the structure) is
substituted with many organic groups o~ alkyl,
methyl, and phenyl without loss of the capacity to
intercalate because the substituents can be
positioned in the groove of the DNA molecule upon
binding. A representative M}RAGE pharmaceutical is
; 15 ethidium bromide derivatived with a Mossbauer isotope
where the bond between the Mossbauer atom and the
rest o~ the molecule is of high enough energy to
permit the Moæsbauer phenomenon to occur.
DNA binding molecule3 such a~ those in Table 6
are darivatized with Mossbauer absorber isotopes such
a~ those in Table 7 yieldinq MIRAGE pharmaceuticals.
r Some representative structure~ are given with
- references to their synthetic pathway a~ follows.
1) A covalent bond directly between a Mossbauer
atom and a DNA binding molecule as prepared by
t~e synthetic pathway for compound 16 o the
Esemplary Material.
2) A chelating functionality covalently attached to
a DNA blnding molecule and a chelation bond
between the chelating ~unctionality and a
Mo~sbauer atom a~ propared by the synthetic
pathway for compound 153 of the E~emplary
Material.
3) A covalent or organometallic bond between a DNA
blnding molecule and a Mossbauer organometallic
3g
- 29 ~
molecule where bonding is with the orqanie part
o the organometallic molecule in the case of a
: covalent bond and with the Moss~auer metal atom
in the case of an organometallic bond as
prepared by the synthetic pathways for
compounds 100 and 25, respectively, of the
Exemplary Material.
4) An organic molecule covalently bound to a
Mossbauer nonmetal atom covalently ~ound to a
DNA binding molecule as prepared by the
. synthetic pathway for compound 38 of t~
Esemplary Material.
S) A nonmetal Mossbauer atom covalently bound to an
organic molecule covalently bound to a DNA
binding molecule as prepared by the synthetic
~-, pathway for compound 45 of the Esemplary
Material.
6) A covalent bond betweQn a D~A binding molecule
and an organic molecule to whlch a Moæsbauer
atom is attached by chelat~on with a chelate
covalently attached to the organic molecule as
prepared b~ tho ~ynthet~c pathway for
. compound 89 of the Esemplary Material~
7~ The D~A binding molecule having a coordinate or
organometalllc bond di~ectly with the Mossbauer
atom as prepared by the synthetic pathways for
compounds 90 and 60, rospectively of the
E~emplary Material.
J~ 3
-- 30 --
Takle 6 - DN~ Bin~inq Molecules
Phenosaf ranine
~ H N/~N~NH2l Cl-
~ 0 ~ 9
- 30a -
Table 6 - çontiFIued
Triostin ~
:~`' NH2
O~ CH3
HNCHCO~ÇHCOl`;lf~HCONÇHCOO~ H2
3. H3C fH HCCH3
. ' S
~1
H3C ~;H2 CH3
CH20CO~HNCO HI~ICOCHNHCOI '~
H3CCH CH3 C--
R ~N~/
NH2
~U~
` - 30b -
Table Ç - conti~u~d
Anthracycline glycosides
( Dauno rubicin)
O
o o ~CH~
H
Adriamycin H~
NH2 H
o Ho ~ CH20H.
OH
H
HO~
NH2 H
- 31 -
Table 6 - cQn~inued
~ogalamycin
~H3
- O O
o~OCH3
H3C~H3
CH~
Mlthram~rcin S~7~
~o~
~' ~o~$
2~3~S039
- 31a -
: Ta~le 6 - cont~
Chromomyc i n A3
p IDCt ~3
- HO7~
~CH3 \[~H3,~OCH3
H ~C~
H~O
_C o_l30H
HO--<
. ~ Ho~CH3
... .
- 31b -
.^ T~kle 6A- cont~
Phenoxazone Antibiotics (Actinomycin D)
L-Pr~ L~M-V~ L-P~ ~;Yd
D~Y~ ~0 D-V ~o
L- ~ L-T~
C=~ C=~
~"N~,~
~0~o
C~
,,
:,
u~
- 32 _
T~ 6 -_ continu~d.
Acridine
Acridinylmethanesul- 3 ~ S O CH
phonanilide ~ 2 3
NH
~3
H ~ CL
Dlacridine
, ~ ~( ~
N~ll[CH2l3~[cH2l,~lCH2~3~_~N
~OCH 3 H3CO
. ~ 20~'~03~3
- 32~ -
Tabl~ ~ - co~inue~
Prof lavine
W2 N~N~NH~
Rhodanine
~ 0
~COCH2CH3
H li~NCH2CH3
~0~5~3~
- 33 -
Tabl~ 6 - ~ontinu~
Acriflavine
HzN~NH z
8-Aminoquinoline
NH2
Cl ~,~N~
Chloroquine ~
N H ~ CH2CH 3
H3C--CHICH2]3N
~CH2CH3
2-Hydro~yethanethiolato(2,2',2''-terpyridine)-
platinum (II) ~ ~
N~
~sPt~SCH2CH20H
~-
6_~
:'
- 34 -
Table 6 - continued
Naphtholthiopheneethanolamine
Cl~g
~HCH2-N/--~>
o ~J
- Phenathridine
(Ethidium Bromide) H ~ N~2
HZN~N--CH2CH3
~ Br e
W1 N~
Phenanothroline ~
CH3
E11ipticene ~-H e
H CH3
~,
":
~: .
- 35 -
Ta~e 6_- c~ntinued
2-Methyi-9-hydroxyellipticine
CH3
H~0H Xe
Tilorone H CH3
CH3CH2~ 2 2~0CH CH ~CH2cH3
Thio~anthenone O HNlCH ] N~CH2cH3
CH3
P~oralen
,;. o5Q~
20C~ t)39
-- 36 --
Table 6 - co~inued
Bleomycin
o
~NH2 NH2
~H~N~2
H2~; j~;N~
HO~ H ~Ithiazole
~H
HO
O~NH2
R = tenninal amine
21)~39
- 36a -
Table 6 - çon~inued
Distamycin A
=O
. I
--Z
~ l
_ O
~-Z~
0=~
I
-Z~
,: O ~
:,' .
.
3r~(~3
- 36b -
Table 6 -_c~ntinued
Net rops i n
I z
_,
I Z
~ -Z~
:~ W
= Tn
,' ~ z~
W ~
0~
: :. T
1"3
- 36c -
T~ble 5~ _ço~inued
..
Hydroxystilbamidine
;~ I
.~
~I
11
~ I
I ~f
N
.
''................. ,
:' . ' ' ' .
SV3~3
-- 37 --
Table ~ - cont~ued
~erenil ~ ~ H2 ~ Cl ~3
1~ Cl ~ NH2
~ ~N~ ,
DAPI HN H
HzN~ NH
: H
Hoech~t 33258
H3C-N N~N
H J~OH
}rehdiamine A H
VNHZ
.
H;~N V~J
.
, `.
. ,
, ;'~ " , '
5~`3
-- 38 --
Table Ç - c~ntin~ ed
Dipyrandium --CH3
Leteoslcl~-n ~H3
~ ~ CH3
M~tomycin C
o o CH30
HzN~OUNHz
,:, O
. NH
' '
''' ,
:`'' .
:. .
- 39 -
Table 6 - con~inued
Pyrrolo-(1,4)-benzodiazepine Anti~iotiCs
(Anthramycin) OH H oH
~ C~c~~,NH2
Sibiromycin
~3 C ~ ~C ~ \ C ~
Nitrogen Mustard ~ 3
(Mechlorethamine)
CH2CH2,Cl
- CH3N~
. ~CH2CH2Cl
Alkyl Sulfonate
(Bulsulfan)
, ~ O
CH3~!o[cH2cH2l2o~cH3
, , O ' O
- .
O ~ 3
- 40 -
Ta~le 6 - continued
Nitrosourea
(Carmustine) Cl CH2cH2~ NHcH2c~2
NO
Ethylenimine
(Triethylene Thiophosphoramide) S
DN 1~ N
~\
N-2-Acetylaminof luorene O
~NHeCH3
Benzo [a] pyrene
;
`:,
.'~''''" .
- 41 -
Table Ç_- ~Qntin~
cis-DiamminediChloroplatinum (II~
N~J3
NH3--lS5~t_Cl
' Hedamycin
C4,Hs201lN2
Rubiflavin
~3H29N~5
.
. Stretonigrin
H2N~,N eOH
.' ' H2N~CH3
~OH
~OCH3
CH3
''''
:
, . .
~J~
- 41a -
Table 6 = contin~ed
Neocarzinostatin
Ala-Ala-Pr~-Thr-Ala-Thr-~lal-Thr-Pro-
Se~-Se~-G3 y-Leu-Asp~Gly-Val-V~l-Lys-
Val-Al~-Gly-Ala-Gly-Leu-G~ n-Ala-Gly Thr
Ala-Trp-Asp-Val-Gly-Gtn-Cys-Ala-Se~-
Val-Asn-Thr-Gly-Val-Leu-Trp-Asn-
Se~-Val-Thr-Ala-Ala-Gly-Ser-Ala-Cys-
Asn-Prs-Ala-Asn-Phe-Ser-Leu-Thr-V~l-
Arg-Arg-Ser-Ph~-Glu-Gly-Phe-L~u-Phe-
Asp-Gly-Thr-Arg-Trp-Gly -Thr-V~l-Asn-
Cy~-Thr-Thr-Ala-Ala-Cys-Gln-Val Gly-Leu-
er-Asp-Ala-Ala-Gly-Glu-Pro-Val-Ala
lle-Ser-Phe-Asn
...
.;..
, . ,
.
I r~
., .
'
)3~
-- 42 --
TABLE 7'
Absorber
~Yb -- l'r6~,m
159.rb _ l59Gd lsgDy
16S~o -- lt5Dy 16S~b
231pa -- 231Th 231~
157Gd -- ls7Eu lS7To
16~Er -- 16~Ho l~m
1~8E~ 6~Ho 16~m
Tc99 -- .Uo Tc99
GdlS0 _ EulS~ Tb15
~dlS~ _ Eul5~ Tbl5~
E~1877 -- ~ol~7 T~1~7
6~ ol70 Tml70
s~lS2 -- p5"152 EUlS2m EUlS2
7~ ~,u17tm T~,17t Lu
Tml59 -- Erl~9 Ybl59
V23S -- pu2~2
S,151 pmlS
. '~
.
~35~3~
-- 43 --
TA13LE r(Continued~
Al~sorber _ Source( )
S~ 53 -- D~alS3
62Sm~S4 -- p ~15~ EuliS~
p~l41 _ c~l4a ~dl4
oS18~ 18~ 1~18~
o~l88 R~188 ~,188
Htl77 Lul77m Tal17 Lu177 Hfl77m
Lul7S -- Yb1~S Hrl7s
ad~60 -- Eu160
Hsl7t L~178 Ta~78 Hf 178m
GdlSJ E~lSS TblS8
E~,166 _ RO156m Tml~ Hol66
csl33 L~l33 B~133 x~l33
~Yb 174mTm 174LU 174Tm
. ~7Z~ -- 67Zu 67a~
172yb -- 172Tm 172~ u
., 17~ l7lTm l7lLu
170Yb 170Tm 170Lu
: ' :
, ~, .
339
-- 44 --
TABLE 7(C~ntinu~
Absorb~r _ S~ur~e(s?
Xo _ 131~ 3l~e
188w 18B~ 18~Re
18~W l~a 18~mR.~ 184 R.
la~W 183~a 183
182w 182T~ 182R
180w mTa 180R~ 180~8
32Ttl(~28Ra~ _ 236u
236u 236p~, 240p~ 236Np
181~ 181Ht 181W
125~,~ 125sb 1251 125~e
7p 147Nd
9Sm ~l~SNd) _ 1~9p~ 1~9Eo
IolRu -- 101~c lOImRh lOlRh
99Ru -- 99Sc 99mR~ 99Rh
l9Spt -- m~ lg5~u 1951R 19Sm pt
~7Pm ~147Sm) _ l~7Nd 147p 147Eu
90~ 89R~ 18~ 18~og
2C)~0;~9
-- 45 --
TA81,E 7tl:ontinued)
Absorber~
Np ( P~) -- 237~ 2~1Am237pu
6INI -- 61co 61cu
83K 83B~ 8SRb83m~
193~ 1930s 193pt
, 19~ lglos l91pt
201Hg ~ ~Au 201
180Ht 180Lu mT~180Ta 180
139L~ _ 139E~ 139CB
187R 187W
23~'U mp~ 23Spu234Np 234p~
',';
239PU -- 2S9Np 2Ucm~39Am
90~s 1 OR. 190~90mOg
~97Au -- 19~pt l97
'
160~y -- 180Tb 180Ho
-
-- 46 --
TA3LE 7(Cont~nued)
Absorber
lSSGd lSS~u lS5Tb
~3G~ _ 73C~ 73A~
~40 _ 39K(n t) ~ 40X
Am Pu243 Bk2~7
~45Nd -- 145pr 14Spm
lSlEU -- lS3sm 153Gd
129t ~129X,) _ 129mT~ 129mx
1195" ~ tn l~9sb Sn 1 l9In
S7F~ S7Mn 57Co
l~lEu - 151sm lSlGd
l2gx~ t 1~9C~ 129~c
l~Dy l~b lB~Ho
lBlDy -- lBlTb lBlHo
162Dy 1621,b lB2~o
117sn 117m5n 117mIn 117I 1175b
5~3
-- aS7 --
TA3LE 7tContinued)
121sb ~in 121Sn 121mTd 121re
12~1 -- 127T~ 12
1291 -- l29TQ 129m
133B~ ~ 133L,~ 133mBa
l~Spm -- 145sm
147sm 147Pm 147Eu
'
~;
3~
- 48 -
~9,~
The materials which are listed b~low are
representative esamples of possible MIRAGE dru~s
which can be synthesized by the deri~atization o~
known D~A bindin~ materials and known Mossbauer
absorber isotopes from Tables 6 and 7, r2s~ectively
- to yield th~ representative struc~ures given in the
: Structure Section. The following e~amples o
reaction pathways are intended to b~ esemplary and
other pathways can be devised by one skilled in the
art. Furthermora, only a representative number o
MIRAGE pharmaceuticals are shown and a va~t number of
other MIRAGE pharmaceuticals can be made by one
skilled in the art followinq the guide lines hsrein
disclosed.
r And, the disclosed MIR~GE pharmaceuticals and
representative structure~ disclosed i~ tho Structure
Section can be ~odified to further MIRAG~
pharmaceuticals to improve properties such as
permeability to cells, ~olubil~ty, and enhanced
selectivity by addition of functional groups by one
skilled in the art. Repres~ntative functional groups
include alkyl, cycloalkyl, alkosycarbonyl, cyano,
carbamoyl, heterocyclic ring~ containing C, 0, N, S,
sulo, 3ulfamoyl, alkosysulfonyl, phosphono,
hydrosyl, h~log~n, alkoxy, alkylthiol, acylo~y, aryl,
alkenylp aliphatic, acyl, carbo~yl, am~no,
cyanoalkosy, diazoniu~, c~rbosyalkylcarbosamido,
alkenyl thio, cyanoalkosycarbonyl,
30 carbamoylalkosycarbonyl, alkosy carbonylamino,
cyanoalkylamino, alkosy c~rbonylalkylamino,
~ulfoalkylamino, alkylcarbonylosy, cyanoalkyl,
carbonylosy, carbosyalkylthio, arylamino,
h~teroarylamino, alkosycarbonyl, alkylcarbonylory,
35 carbosyalko~y, cyanoalkosy, alkosycarbonylalko~y,
~v~
-- 49 --
carbamoylalkoxy, carbamoylalkyl carbonyloxy,
sulfoalko~y, nitro, alkoxyaryl, haloqenaryl,
aminoaryl, alkylaminoaryl, tolyl, alkenylaryl,
allylaryl, alkenyloxyaryl, allylo~yaryl,
allyloxyaryl, cyanoaryl, carbamoylaryl, carbosyaryl,
alko~ycarbonylaryl, alkylcarbonyo~yaryl, sulfoaryl,
`- alkosysulfoaryl, sulfamoylaryl, and nitroaryl.
GENER~ Sy~T~ c ~ aY~
10The ollowi~g synthetic reactions are esemplary
of general synthetic reactions to be used to link a
- Mossbauer absorber atom such as one from Table 7 with
a DNA binding molecule such as one from Table 6.
General reactions involving general organic
chemistry such as Wittig reactions, nucleophilic
substitution reactions, tosylate reactions,
Friedel-Crafts alkylations and acylations, etc.
appear in the EYemplary Material and are generally
known to one skilled in the art. These same t~pes of
reactions can be used by one skilled in the art to
derivatize the DNA binding molecules of Table 6 to
produce the starting materials generally shown in the
Esemplary Material.
In some cases which are esemplified in the
E~emplary Material Grignard reagents are prepared of
the D~A binding molecules or derivatizing organic or
organometallic molecules containing a Mossbauer
atom. The Grignard reagents can be prepared by
halogenation using a halogen gas and an initiator or
by using a halogen gas and a catalyst such as FeX3
where X is halogen followed by reaction with
m~gnesium.
R ~X~h~ Rx ~R~x
R~ ~R~Y~
R = ~y/ J X hG I~
~5~3.~3
- 50 -
For Grignard reagents as well as other compounds
formed by the above synthetic pathways, multiple side
products of the materials shown in the E~emplary
Material are possible and are often desirable.
However, the reactions shown are intended to be
exemplary o~ the types of reactions possible and are
in no way intended to be e~haustive.
GeneraL Re~çtiQn~Q~ Tin
r~
R3SnCl ~ R'~gCl ~ ~3SnR'
R3SnNR2~ ~ R3SnR"
R"=aryl
(CQmEIsh~ive Qr~anom~allic ~hemistr~, Sir Geoffrey
Wilkinson, Editor, (1982), Vol. 12, Chapter 11)
incorporated by reference.
Ge~al Rç~ti~ns of An~imony
1 .)SbCl3 in HCl ~ llaNO2 ~ RSbO~112 R'
Z 2.) Cu bronze in NaOH(aq) ~j
R R=aryl R )~50
bCI~ ~ R'
R R R'-1 ~r~
~,~
,
L
.
2~)0~ 3
- 51 -
(O~qanomçtallic ComPounds Methods of SYnthesis
Phy~ical_Constants and Chemical Reactions, Michael
Dubb, Editor, 2nd Edition, Vol. III, (1968),
pp. 653-925) incorporated by reference.
Ge~eral Reactions of Tellurium
~Li ~ Te ~ ~LiTe lRX
@~TeR R-alkyl,vinyl, aryl
(Seebach, P.; ~eck, A.L., Chem. Ber., 108, (1975),
314-321) incorporated by reference.
General Reaction~ of Germani~m
R3GeLi ~R'Cl ~ R3GeR'
(Comprehen~ive Qrganometal ~ , Sir Geoffrey
Wilkinson, Editor, (1982), Vol. 2, Chapter 10)
incorporated by reference.
Ge~L_l Re~tion~ of Me~cury
R ~HgCl NaoAc
R~ viny7, aryl
R~ ~ HgX~ ~sRH9x
r-1=L~ g
(Compreh~nsive Organometallic ChemL~try, Sir Geoffrey
Wilkinson, Editor, (1982), Vol. 2, Chapter 17)
incorporated by reference.
2~'~SO~
-- 52 --
.~ G~ne~Reac~iQns o~ I~
R N_N(~ 6r kIC~ ) R I
O C
,~ ~ a f y /
(Org~~ Çhemis~ry, Fessenden, ~.J., Fe~senden, J.S.,
(1979) p. 728) incorporated by reference.
Representative esamples of reactions which yield
DNA binding MIRAGE pharmaceuticals are given in the
following esamples. These esamples are not to be
taken as an exhaustive listing, but only illustrative
of the possibilities accord1nq to the present
invention.
- 53 -
Ex~ple l
Compound 5 is prepared as follows:
Trimethylstannylchloride 1, is reacted with
imine 2, to form aminotin compound 3. The
aminotin 3, i5 reacted with psoralen 4 to form the
tin derivatized psoralen product 5 where the reaction
between 3 and 4 is as described in Compreh~nsiv~
Oraanometallic _Chemistry, Sir Geoffrey Wilkinson,
Editor, (1982), Vol. 2, p. 601, incorporated by
reference. Substitution at other aryl sites is
likely, and these products are also espected to have
utility. - ~ /H
(CH ) ~9 Sn H + <~-~- C\<~
[2]
1 IH3]3
0
~31 14]
0~ NCH2-~
[CH3]3 [5] ¦~¦
:,
- 54 -
ExamPle_2
Compound 8 is prepared as follows:
The Grignard reagent 6, which is an
8-aminoquinoline derivative, is reacted with
trimethylstannylchloride 7, to give the tin
derivatized quinoline product 8 where the reaction
between 6 and 7 is described in Comprehensive
O~q~nometallic ~emis~ry, Sir Geoffrey Wilkinson,
Editor, (1982), Vol. 2, pp. 530-532 incorporated by
reference.
~9SnCI
N H ~H2CH2~1gC1 ~CH3]3
H3C CHlCH213N~ ~ 17]
t6]
N H / CH2CH~ "9Sn
t8]
03~
-- ss --
ExamPl~ 3
Compound 11 is prepared as follows:
Actinomycin D, 9, is reacted with tetraalkyltin
compound 10 to form the tin derivatized Actinomycin D
product 11.
L Iro L I Yd Lt o ~leY~I
~-Vd ~o o-V~lo
L-~lr ~L~ 9
C=~ ~=0 1
~N~ [CH3]3
~o~O [10]
a~ CN,
[91
L I 7V~l L~Pro ~V~I
D-Y-l ~0 D~
L-~lr L~ r
C_~ e~O
rcH2~snlcH
, ~ a~,
[111
:'
.: '
3g
- 56 -
ExamRle 4
Compound 13 is prepared as follows:
Trimethystannylchloride is reacted with a
Grignard reagent derivative of Irehdiamine A to give
product 13.
N1CH3]2
~,~, .,. ICH311'9SnCI
~71
~`f~f ~CH2t~g~:1 ,~,,
3l2N~J
1121
. . .
VNlCH3~2
.
~ ~ ~CH2 "9SnlCH3]3
1CH3I2N~J
~13]
.
2(~5(~39
- 57 -
Exam~le 5
Compound 16 is prepared as follows:
A Grignard reagent of phenosafranin is reacted
with trim~thylstannylchloride 7 to give product 16.
CH3l2N ~3~N[CH3] Cl-
[CH3l3"9SnC
g ~141
; CH312NJ~3~N[CH3l ¦ Cl
~5Sn[CH313
161
20~
- 58 -
E~amPle 6
Compound 19 is prepared as follows:
Proflavine 17, is reacted with antimony
trichloride in the presence of HCl and NaNo2. The
product is hydrolyzed and the diazonium salt
decomposed by reaction with NaOH and copper bronze to
yield the antimony derivatized acridine 19 according
to the method of O'Donnell, G.J., Iowa State Coll. J.
Sci., 20, 34-6 ~1945); CA 40. 4689; Ph.D. Thesis
No. 760, submitted Aug. 23, 1944 at Iowa State
College, incorporated by reference.
~ ~ 1.1 HCI 0
H2NJ~N~NH2 SbC13 2.1 NaOH~~
118] Cu bronze
17]
.
23 Sb ~ IZISbo3Hz
119]
20~03.3
- 59 -
ExamF~le 7
Compound 23 is prepared as follows:
1,2-dihydroxybenzene is reacted with antimony
trichloride in the presence of HC1 to give
2-chloro-1,3,2,-benzodio~astibole 21. Nucleophilic con
densation of hydroxy derivatized ethidium bromide 22,
with compound 21 yields the antimony derivatized
ethidium bromide product 23. Substitution products
at the amino groups are also anticipated, and utility
of these products is e~pected.
The synthetic pathway of product 23 is in
general described in The Heterocyclic Derivatives of
Pho~korus,_ Arsenic. An~imony. and ~ismuth,
Frederick G. Mann, 2nd Ed., (1970~ pp. 615-619,
incorporated by reference.
~j_OH ~ l21SbC13 HCl ~
~OH 1181 ~o,SbCI
~20] ~21]
~0~3~)3~
- 59a -
E~amplç 7 - continued
~1 .~
~,SbCI o~ NH2
[21] ~
: H2NJ~N--CH2CH3
~,NH2 ~1 122]
H2N~5N--CH2CH~ H
l2~S'b~ [231
':
~,
., ,
~`` .
.
5(3~
~ 60 -
Examp~e 8
Compound 25 is prepared as follows:
2-chloro-1,3,2-benzodioxasti~ole 21, is reacted
with the anthracycline, doxorubicin 24, to give the
antimony derivatized do~orubicin product 25.
Substitution products of the sugar hydroxyl grsups
are anticipated, and utility of these side products
is e~pected. O o
,SbCl o o ~ C~20H
~21] ~ ~ OH
CH3 ~
H~
O NH2 H
H ~CH20H ~241
O O ~
` ~OH
. H
H~
NH2 H
~o~
- 61 -
E~ample 9
Compound 28 is prepared as follows:
Compound 26, 2,2'-biphenyldilithium is condensed
with aryldihalostibine 27, in benzene under reflux to
yield the product 28.
~261 121SbCl2
[271
: ~21Sb.... _~
~ ~28]
.'''' .
.
~, .
2Q~'3(~9
- 62 -
Example lO
Compound 31 is prepared as follows:
N,N'-dimethyl-4,4'-diamino-2,2'-oxybis (phenylenem
agnesiumbromide) is condensed with primary
dihalostibine 27, in ether, benzene, dioxane, or
their mixtures to give product 310
[CH ~ 9M~
SbC12
~CH~I N)~SbX~N[CH3]127l
.".,.
~
~J 1311.
.:
~'' ' .
:`
~ ., ,
,;~ 3~3
- 63 -
Exam~1Q_ll
Compound 34 is prepared as follows:
Luteoskyrin 32, is reacted with
2-chloro-1,3,2-benzo- dioxastibole 21, to give the
product 34. Substitution products of other hydroxyl
groups is expected and utility is espected for many
of these products.
HO OH
H~ [21~
H~CH3 --
OH O OH ~321
HO OH
H~CH3
.. ~C1~13
OH O IZIS'b--T~
~;~4] ~--W
'
1'.
",
~ . . .
,. . .
- 64 -
E~amDlQ_lZ
Compound 38 is prepared as follows:
Phenyllithium is reacted with tellurium to give
adduct 36 which is reacted with the phenanthridine 37
to give the tellurium derivatized product 38
according to the reaction of Seebach, D.; Beck, A.L.,
Chem. Ber. 108, (1975) pp. 314-321, incorporated by
reference.
j l lZsTe~l2sTeL;
~35] [3~]
~_N ICH3I2
ICH312NJ~HZCH, 6
~371 [36]
~N ICH312
ICHJIZN~e ,~e
,d~,
~J 13al
:
.
'.
. .
/
u~
- 65 -
E~a~ple 13
Compound 40 is prepared as follows:
1,8-dilithium naphthalene 39, is reacted with
tallurium to yield the product 40 according to the
method of Marfat, A., et al, Journal of the American
Chemical Society, 99, (1977) pp. 255-256,
:incorporated hy reference.
Lj L~ 125Te~e
'2sTe~
[391 [40
E~ample 14
Compound 42 is prepared as follows:
3,6-dichloroacridine 41, i~ reacted with lithium
followed by tellurium and methylchloride to gi~e the
alkyl tellurium derivatized acridine product 42.
~ l.]Ll/THF
Cl ~N~ 7 I'~5Te
14tl
' 125T¢~D~125T~e
[42] CH3
,
.
. .
~5(~a3
~Q~
Compound 45 is prepared as follows:
Kanchanomycin 43 is reacted with the dialkyl
telluride 44 to give the product 45. Additional
products substitu~ed at the hydro~yl groups are
anticipated, and utility of these products is
expected. ~
T
o
[43] ~0
CH30~J
H3~,o~
H N~ `=
~_ O~,OH
CH30
51
5(33~
E~m~le 16
Compound 47 is prepared as follows:
Diacridine 46 is reacted with lithium followed
by tellurium and methylchloride to give the
methyltellurium derivatized biacridin~ product 47.
N~[CH213~1CH2]4~1CH2]3~ ~-6;~,N
~CH3 CH3 CH3 CH3
OCH 3 ~461 H3CO
CH~ 1.1Li~THF
~25f e ~1~25Te --~
CH3CI ~5TeCH3
.. N~qJlcH2l3~lcHzl4~lcH2l3~ N
,~CH3 CH3 CH3 CH3
OCH 3 147] H3CO
~'.
,
,.~.
~0~ 3
-- 68 --
E~ample 17
Compound 50 is prepared as follows:
- Hycanthone 48, is reacted with the tellurium
derivatized phosphonium ylid 49 to give the alkyl
tellurium derivatized thioxanthenone product SO.
~H ] N,CH,CH,
CH20H
[4~3]
,~
~CH2~25Te L-~
:` ~F' [4C~CH3
H3C CH ~
~HZ]2N `CH,CH3
CH20H
.:
- 69 -
Esample 18
Compound 52 is prepared as follows:
Trimethylithium germanide 15, is reacted with
1,2-dichloroethane 30, and
2-chloloethyltrimethylgermanium 33, is isolated ~rom
the product mi~ture which is reacted with Netropsin
to give the product 52. Other substitution products
are anticipated, and are e~pected to be of utility.
[CH31 ~7~G eLi ~ ClCH2CH2Cl
~15] ~30]
ClCH2CH273Ge~CH313
: E331
H2NfiNHCH2fiNH ~3
NH NH N -fjNH ~ ~NHz
CH3 0 ~ jNH--lCH212~NH
. CH~ O
~51]
~ 3' T
. " C~
.':'';
N
;, I
,'i H2N6NHI:H2fiNH ~
I~H NH N -fjNH ~ NH
~i CH3 0 ~ FjNH--~CH2l2~--NH
CH3 0
[52~
3~
- 70 -
Esam~Q 19
Compound 55 is prepared as follows:
The halogenated derivatize of ellipticine 53, is
reacted with trimethyllithium germanide 15, to give
the product 55, according to the method described in
Comp~e~ensive Orqans Me~allic Chemi~try, Sir Geoffrey
Williams, Editor (1982) Vol. 2, Ch. 10, incorporated
- by reference.
CH3 X
H3C~N-CH2Cl
CH3 CH3
~531
lCH31373GeLI
~: ~15] e~,
CH3
H3CG~_CH273GelCH3]
- CH3 CH3 1551
- 71 -
Compound 58 is prepared as follows:
Platinum compound 56 is reacted with
9-hydro~yquinoline in acetic acid to give the
product 58 according to the reaction described by
Kite, K. and Truter, M.R., J. Chem. Soc. (A), 1966,
207, incorporated by referenc2.
O
~CH313'95PtO~CH3
~5~]
~3 CH3~0H
~57]
~CH3]3 5 ~ ~ _ ~ ~ [CH3]3
,,, ~ ~
~58]
3~q3
_ 72 -
- Compound 59, cis-diamminedichloro-platinum{II), is a
compound which binds directly to DNA.
It is synthesized using 19~ Pt as described
in Dhara, S.C., Indian J. Chem., 8, (1970) p. 193,
incorporated by reference.
Nl 13
NH3--19~Pt--Cl
, I
C1
. 159]
.` .
E~mple 22
Compound 60, 2-hydrosyethanethiolato(2,2',2''terpyridin
e) platinum(II) intercalates directly into DNA.
It is synthesized using l~Pt as described in
Jeannette, L.W.; Lippard, S.J.; Vassiliades, G.A. and
Bauer, W.R. (1974), Proc. Nat. Acad. Sci. USA, 71,
3839-3843, incorporated by reference.
~ ~ /~
. : 1~5p~ . SCH2CH20H
N'
60]
~0~ 39
- 7~ -
Exa~ple 23
: Compound 64 is prepared as follows:
Gold compound 61 is reacted with
trimethylphosphonium- ylid 94, and
dimethylchloromethylphosphoniumylid 54, to give
product 62 as described by Schmidbaur, H., and
Franke, R., Inorganica Chimica Acta, 13 (1975) 79-83
~incorporated by reference) with the exception that
dimethylchloromethylphos- phoniummythylid is also
made present with trimethylphos- phoniummethylid and
the desired product is isolated from the reaction
mixture. 62 is reacted with phenanthridine 63, to
give the product 64 where products with substitution
~ at the aniline nitrogens are anticipated and these
: ~ products are e~pected to have utility.
97A¢~ jAu~
CH2C
2[CH312P=CH2 ,~
2[CH3]3P=CH2
` 194]
-- 74 --
E~mple 23 - continu~d
~`, CH2Cl
r CH3 l9, /CH2p~[cH3
H2P~ H3]3
, l62]
~, NH2
H2NJ~ [631
.', ~
~ NHz P~CH313
HzNJ~CH~3
~64]
)3~3
- 75 _
Es~mple 24
Compound 67 is prepared as follows:
Gold ylid compound 65 is reacted with nitrogen
mustard 66 to give the product 67.
: CH2CI
CH3 ~ ~CH2~1cH3]2
: j AU CH2 P~CH3]2
.~` CH2Cl
[6~51
HNlCH2CH2Cl]2
~66]
CH2NlCH2CH2cl]2
CH3 ~CH~PlCH3]2
,'97AU~
CH3 / ~CH2~lCH3]2
CH2NICH2CH2Cl]z
~67]
5U~
-- 76 --
E~a,~2 ~
Compound 72 is prepared as follows:
Pyrrole adduct 68 is mercurated by the reaction
described in Comprehensiv~ Orqanometallic Chemistry,
Sir Geoffrey Wilkinson, Editor, (1982), Vol. 2,
p~ 871 (incorporated by reference~ to give adduct 69
which is reacted with osalyl chloride to give acid
chloride 70. The acid chloride is reacted with
v amine 71 to give the mercurated derivative of
Distamycin A 72.
.' o
HCNH~3_gOH excess Z~9c12
. CH3 NaOAc
~681
0~ 201Hgl
Cl201Hg~I IOH
CH3
1691
O ZOlHgl
HCN~ Cl
. CH3
170] ~
fiNH 7~ NH2
CH3 O ~ -fiNH--~CH2lzt! ~H
CH3 ~711
.
"''
o jO~9
- 76a -
Exanlp~Q 25 _- ~ontinued
;
o
~ o
j \ I
. ~
<~--Z ~
~ _
w r
n
z
/:~ I
~ _z
W
,, o=n
I
--Z
W
03~ .
I
T
N
. ~
. - T N
3~
- 77 -
E~ample 26
Compound 74 is prepared as follows:
Miracil 73 is mercurated to give product 74.
Mixtures of mercuration products are anticipated, and
these products are e~pected to be of utility.
HN[CH ] N~CH2cH3
~3
CH3
[73]
HN~CH ] N~CH2CH3
Cl20~Hg~¢~
CH3
~741
3~
- 78 -
E~m~lç 27
Compound 76 is prepared as follows:
N-acetylaminofluorene 75 is mercurated to give
product 76. Mi~tures of mercuration products are
anticipated and th2se products are e~pected to be cf
utility.
~3_NH~CH3 Z~ HgCI2
NaOAc
E751
~NH~CH3
, Cl20lHg_~
176]
3~3
-- 7g --
E~ample 2~
~ompound 82 is prepared as follows:
Rutheniumtrichloride is reacted with
cyclopentadiene to give ruthenocene 77, which is
acylated to give ketone 78. Both reactions appear in
ComPrehensive _Organomçtalli~ _ÇhsmistrY, Sir Geoffrey
Wilkinson, Editor, (1982), Vol. 4, pp. 7S4-773,
incorporated by reference. Adduct 78 is reduced with
lithium aluminum hydride to give alcohol 79 which is
reacted with p-toluenesulphonylchloride 123 to give
tosylate 80. Adduct 80 is reacted with
Adriamycin 81, to give product 82. Substitution of
other nucleophilic sites of Adriamycin is
anticipated, and these products are expected to be of
utility.
C~H5 OE7 CA;CI~CI
1771 H
O O
LiAlH4 ~ CCH3
781 l79]
O
H3C~Cl
ll2~]
3~
-- 80 --
E:~ample 28 ~cQntinued)
O
CH3 a o ~ cH2oH
- ~CH ~OH
= O ~ y
180] [~ ~ HO~
NH2 H
~81
H
HO~ 1821
N~2 H
.;,,
. .
2~50;~g
- 81 -
E~amelQ_2~
Compound 85 is prepared as follows:
Alkyl halogen deriva~ive of ruthenocene 83 which
is prepared from 79 by treatment with phosphorous
trichloride is reacted with Sibiromycin 84, to qive
the product 85 which is the preferred substitution
product.
~CH2Cl
99RU
183]
H3C ~j~3C~ N_~H
H3 O~N q ~H
H \ ~C$ ~CH3
184] H~
:,
~C~ CH3
1851 H~
~û~5~
- 82 -
Example 30
Compound 86 which is a coordinate compound of
ruthenium and phenanthroline intercalates DNA
directly.
It is synthesized using 9~Ru as described in
Comprehensive Orqanome~allic Chemistry, Sir Geoffrey
Wilkinson, Editor, (1982), Vol. 4, pp. 704-705,
incorporated by reference.
OC
OC~3
~861
~0~ 03~3
- 83 -
Ex~mple 31
Compound 89 is prepared as follows:
Quinacrine derivative 87 is reacted with a
chloromethyl derivative of
diethlenetriaminepentaacetic acid 88, to give the
product 89 which is the preferred product of the
possible mixture involving substitution of the other
nucleophilic sites.
~H3
HC-~cH213NH2
HN
H3C~
~Cl
1871
CH2Cl
2cc~2l2NcH2cH2~cHcH2NlcH2coo-l2
CH2COO- --
~881 2+
Ln Acn~ N~
~00~(3~
- 83a -
Exame~5L~
O
~.) N
X Z
N O
HC-[CH2l3NH ~ _~Z,
H3C~CI ~
C~
N
~8gl
N~ N
Ln=l45Ndll4sprJl47pr~l49sm~l5lsm~52sm~ls3sm~l54sm~
EU~'53Eu~ls4Gd~ls5Gd~l56Gd~ls7Gd 15BGd IBOGd 159Tb
160Dy 161Dy 1~2CJy ~33Dy,l~ Dy,lG5Ho,1~4Er,16~Er~l67Er~
~Er,'70Er,l~lyb,i72yb 174Yb 17~yb;
A~c9p l~T~ho~ ,231pa ,23~ 232U4~ 237N 4
.,
~0~
- 84 -
~ma~
Compound 90 is a coordinate compound of an actinide
and 8-hydro~yquinoline which intercalates DNA
directly.
90 is synthesized using the indicated Mossbauer
isotopes by the procedures referenced in The Actinide
Eleme~S~ K.W. Bagnall, (1972) pp. 211-229,
incorporated by reference.
~Z ~o_~
.~ ~.
190]
AC= 234U4~ 23BU4 232Th4
~0050
- 85 -
E~ e 33
Compound 93 is prepared as follows:
Alkyl halogen derivatied Bis~arene) tungsten
compound 91, which is synthesized as described in
ComPrehensive Orqanometalliç Chemis~ry, Geoffrey
Wilkinson, Editor, (1982), Vol. 3, pp. 1356-1359
(incorporated by reference) with the modifications o~
using benzene and methyl substituted benzene
following the synthetic route described in the above
reference. The monomethyl product is isolated from
the product mixture and chlorinated to give 91 or
chloromethylbenzene is used in the referenced
synthesis with isolation of 91 which is reacted with
alcohol derivative of 8-aminoquinoline 92, to give
the product 93 where other substitution products are
anticipated, and utility is expected.
~CH2CI ~ =~
W NH2
<~> ~Nq
~411 ~ OH
N H / CH2CH2
H3C-CHlCHz]3N~
es21 CH2CH3
,
NHz
O CHz~>
N H / CH2CH2
H3C-CH~CH2]3N
~CHzCH3
[931
W='elW, 182W 1~3W l~w
.: .
.,
~305(33~
- 86 -
Exa~ple 34
Compound 96 is prepared as follows:
Alkyl halogen derivatized bis(arene) tungsten
compound 91, is reacted with the carboxylate
derivatized Anthramycin 95, to give the product 96
which is the preferred product of the mixture which
could result from substitution at the hydroxyl groups.
<~CH2Cl +
W
~> O -
[91] ~
C$ ~C NH2
~951 H~ o
W ~C~ ClNH2
~96] H~ o
,:`
,~ .
.... . .
- 87 -
Ex~mple ~5
Compound 100 is prepared as follows:
Osmocene 97, is prepared from
osmiumtetrachloride and sodium pentadienide as
described in ComPrehensive Oraanometallic ChemistrY,
Geoffrey Wilkinson, Editor, (1982), Vol. 4, p. 1018,
incorporated by reference. Osmocene is acylated to
give ~etone 98 as described in the above reference.
98 is reacted with an ylid derivative of acridine 99,
to give the product 100. ~
OsCl ~ Na W ~~
~97]
oS ~ CH3CCl AICI3
~CH
. ~ i1
[~3 ]3
[991
`, CH G ,~ os=l8~s,l880s,
H3C ~ o (~ ~lo8~]S,190Os
. ;. , .
..
. . .
39
- 88 -
Example 36
Compound 103 is prepared as follows:
Methylalcohol derivatized osmocene 101, which is
prepared according to the method described in
Comprehensive Or~anome~allic Chemistry, Geoffrey
Wilkinson, Editor, (1982), Vol. 4, p. 1018
(incorporated by reference) is reacted with the
tosylate derivative of Mitomycin, C 102, to give the
product 103.
~CH20H
Os
."' ~
~lOt]
3 ~H2
[102~ NH
O O
H2N~coH~INH2
OE~CH20 CH/~
~ ~tO3] NH
: '
. .
:-' .
:.
;"',
r~ 3
- 89 -
E~am~le 37
Compound 106 is prepared as follows:
The diazonium derivative of Mithramycin 105, is
prepared by treating the amino derivative 104, with
nitrous acid. The diazonium derivative is reacted
with aqueous potassium iodide to give the product 106.
DH
.'~ o~
/~\ H07
~C ~ \~C~
H~; H~ HONO
Ci l~ ~OH
HO~ ~104]
HO CHa
.~
': ,
. . .
.
.; ' ' .
. .
2~)~35~3~
90 --
E2c~mp le 3 7 - cont i nued
a~
/~ H7~ K I [Dq
e~H ~0~
C~,CrCO ~OH
H~
HO;~ Hs
O O~CH
I~--OH
,,'., 5~=~ ~
CH,O~ \ _13OH
HO~ 1271 129
HO~CHs 11061
.,
.
~)Q~
-- 91 --
E~eLç 38
Compound 108 is prepared as follows:
The amino derivative of benzo[a] pyrene 107 is
iodinated by treatment with nitrous acid then aqueous
potassium iodide.
l.]HONO,HCl
2.Kl[a
NH2
Ll07]
. ..
~ 27, 129l
; ~108l
.
,, ,
. - 92 -
.
E~a~ple 3~
Compound 110 is prepared as follows:
The amino derivatized quinoline antibiotic 109,
is iodinated by treatment with nitrous acid and
aqueous potassium iodide to give the product 110.
The reaction is carried out under cold conditions to
prevent hydrolysis of the antibiotic.
NH2
03~J~N~ CH3 HONO,HCl
HNCHCO~ÇHCOl`,l~jHCOhÇHCOO(H
H3C H3C CH HCCH3 2
''
H3 I j:H2 CH3
CH 20CO~HNCOt:~Hl~lCO(~HNHCOI :Hqll I
H~CC,H ClI C=O
[1091 N
,. NH2
":'
.~
... .
2~)~5(~
-- 93 --
E2camp 1 e 3 9 - cont i nued
I
CH3
HNCHCO ÇHCOI`,I~;HCOI~ÇHCOOl H2
CH2 HC, CH3
H3C ~H2 ~CH3
CH20CO~HNCO H~ICOCHNHCOI 'H~ll I
H3CCH CH3 C--
R ~N~/
~110] ~N
.. . I
.
I_lZ7l 129l
2~3~3~3
- 94 -
E~ple 40
Compound 112 is prepared as follows:
Amino derivatized
naphthothiopheneethanolamine 111, is iodinated by
S treatment with nitrous acid and aqueous potassium
iodide to give the product 112.
H2N~ l.]HONO, HCI
Cl \~ ~--~ 2.1K I [aq}
HCH2-N
~llt] o \~
H
.
,~
,.,
~ Cl~
~HCH2 N~
[112]
1_12~l 129l
,,
;.'
- 95 -
E~amPle 41
Compound 115 is prepared as follows:
Hafnium adduct 113 is reacted with 8-hydro~yquinol
ine 114 to gi~e the product 115 as described in
Comp~ehensiv.e Org~nometallic Chemistry, Geoffrey
Wilkinson, Editor, (1982), Vol 3, p. 565
(incorporated by reference) where 113 is prepared as
described in the same reference p. 569.
~ H
Cl --Hf Cl ~
~Nq
1113]
`~ 1114
c~
.','''
¦llS] Hf-176Hf, 177Hf mHf
~.
. . .
~0~3~3
-- g6 --
Example 42
Compound 118 is prepared as follows:
The alkyl chloride hafnium compound 116 which is
prepared by preparing the methyl substituted
bis(cyclo- pentadienyl) hafnium dichloride as
- described in Comprehensive Org~nometalliG Chemistry,
Geoffrey Wilkinson, Editor, (1982), Vol. 3,
pp. 569-570 (incorporated by reference) which is
chlorinated, and 116 is isolated from ths product
misture and is reacted with proflavine 17, to give
the product 118 where the disubstituted product is
anticipated, and utility is expected.
:
. .
CH2CI
.,
Cl -- Hf-- Cl ~ -
.`, ~
11161
H2N~N~ NH2
i 1171
~CHzX)~NH2
Cl Hf - Cl
~ [1181
2(~Q39
- 97 -
E~ampl~ 43
Compound 121 is prepared as follows:
The alkyl chloride hafnium compound 116 is
reacted with Hoechst 33258 120, to give the
product 121.
~CH2Cl
Cl Hf--Cl
__
~lt61
H~C-N N~N OH
Cl ~; Cl
3~3
~ - 98 -
: E~m~lQ 44
Compound 126 is prepared as follows:
-:Tantalum alcohol adduct 122 which is prepared by
using the synthetic route of Wilkinson, G. and
Birmingham, J.M., Journal of the American Chemical
Society~ (1954~, Vol. 76, pp. 42~1-4284 (incorporated
by reference) with the e~ceptions that follow: In
addition to cyclopentadiene, methyl sub~tituted
.cyclopentadiene is used as a starting material to
prepare the methyl-bis-cyclopentadienyl chloride of
tantalum. This compound is chlorinated to yield 127
-which is treated with hydroxide to yield 122. This
alcohol is reacted with
p-toluenesulphonylchloride 123 to form the
tosylate 124 which is reacted with the hydrosy
derivative of psoralen 125, to give the product 126.
,.
HO~ CH2 OH 1I CH3 Y
H O
[1221 11231
~Q~ 3
_ g g _
E~m~le 44 - continued
O
~CH2 O--S ~H3
HO--Ta OH ~ O
[124]
... .
H
125]
0~
OCHz~
~126] HO~OH
H
2Q~5~339
- 100 -
Exam~le 45
Compound 129 is prepared as follows:
The alkyl chloride adduct of tantalum 127, is
reacted with Berenil 128, to give the product 129.
Other substitution products are expected, and utility
is expected.
@~,CH2 Cl
HO Ta -OH
N H2 ~3 ~ NH2 Cl
~ ~N~N~I~
~128]
~ NH2 ~t ~ NH2 Cl 3
HO~ \~N~N,
H
[1291
20~ 3~3
- 101 -
.:
E~a~ple 46
Compound 132 is prepared as follows:
Diphenyldilithium compound 130, is reacted with
iridium adduct 131 to give the product 132 by the
procedure described by ~ardner, S.A., et al, Journal
of Organometallic Chemistry, 60 (1973) 179-188,
incorporated by reference.
~3 , OC~I
1130]
~D
131]
oc3~
11 ~21
I r=~93 Ir, 19l l r
3~3
, .
-: - 102 -
Ex~mEl~ 47
- Compound 137 is prepared as follows:
Iridium adduct 133 is reacted with diazonium
adduct 134 to give the o-metallated adduct 135
according to the method of Farrell, ~.; et al,
Journal of the Chemical Society, Dalton, Trans.,
1977, 2124, incorporated by reference. 135 is
- reacted with phenanthridine 136, to giYe the
product 137 where other substitution products are
anticipated and utility is expected.
~1 ! P~>]
[1~3] e
_~ BF4
ClCH~N~
11~4]
._
.' ~
Cl\pjco ~ ~
[ ~P-N~`CH2CI BF4
~135]
S~3;~
- 103 -
E~c3mple 47 - continued
, ,. ~, NH2
H 2N~N ~ _~
,..~
1 e
S~ BF4
~ca~N~N~H
137
ZHN
,
',
V343
- 104 -
E~m~le 48
Compound 142 is prepared as follows:
- Iridium compound 138 is reacted with Grignard
reagent 139 followed by chlorination to give chloride
adduct 140 according to the procedure of Rausch, M.D.
and Moser, G.A., Inorganic Chemistry, Vol. 13, No. 1,
1974, pp. 11-13, incorporated by reference. 140 is
isolated from the reaction mi~ture and reacted with
:the alkyl amine derivative of psoralen 141, to give
the product 142.
a
Br
13a~ ~
2.lCI2~UY light
o
[ ~P ,~,r ~CH2CI
M X~
.. . CH2NH
r~H2 H2~J~
~r~ 11421
- 105 -
Ex~mele 49
Compound 145 is prepared as follows:
Sodium he~achloroiridium (III) is reacted with
benzo[h] quinoline 143 to give 144 which is reacted
with ~ributylphosphine 119, to give product 145 as
described in Com~rehensive Org~nQmetallic_ Chemistry,
Geoffrey Wilkinson, Editor, (1982) Vol 5, p. 587,
incorporated by reference.
Na~[lrcle]
1143
[~ ~C~
1144]
:~lCH2CH2CH2CH313
11451
CH2CH;!CH2CHs]3
L~ \cl
~ O ~)5 (~3 ~:~
- 106 -
Exa;~ple 5Q
Compound 150 is prepared as follows:
Iridium adduct 146 is reacted with phosphine
compound 147 to give o-metallated adduct 148
according to the procedure described in Çomprehensive
Organomet~llic Chemistry, Geoffrey Wilkinson, Editor,
(1982), Vol. 5, pp. 578-587, incorporated by
reference. 148 is acylated with an acid chloride
derivative of acridine 149, to give the product 150.
Substitution at any of the other aromatic sites can
occur, and any of these side products are of equal
utility.
H - Cl
~;~; 1147]
146]
<~ ~ ]3
148]
N l_
N
'
.
'
... . .
2~t~3.~3
- 107 -
~am~e 5 ~ Qnt i nued
~ AIC~3
[1491.
~]s
g~ [1501
N
~0~
- 108 --
E~mE~le 5~
Compound 153 is prepared as follows:
The crown ether 18-crown-6 151, is reacted with
TiloronP derivative 152, to give the product 153.
o
~QH
Ha~ ~ M~ OH
~o~
CH C~2~c~2cH2o~ocH CH ~,CH~CH2OH
11S2]
O ~p=O
[c~ I O']
~~0
O S
~cH2cH2~c~ocH2cH2~ll`cH CH
CH~C~2 ~ 2 3
o
~153~ K l33CS
28t~ 3~
- 109 -
Ex,ample S2
Compo~nd 158 is prepared as follows:
Acid chloride derivatized ferrocene 154, is
prepared by treatment of the ferrocene carboxylic
acid whose synthesis is described in Comprehensive
Orqanometallic ChemistrY, Geoffrey Wilkinson, Editor,
t1982), Vol. 4, p. ~76 (incorporated by reference)
with o~alyl chloride; 154 is reacted with
1,3,4-butanetriol 155, followed by isolation of 156
from the reaction mixture. Compound 156 is reacted
with methylsulfonyl chloride 157 to give the
product 158 which is a derivative of Bulsulfan.
'
~Cl H
57Fe ~ HOCH2~CH2CH20H
~15
[tS4]
~OC~ 3
-- 110 --
E~amp1~ ~- continued
O
O O
Fe 'CH3~CI
OE~ [157]
[156]
ON_~CH3
I o
O
~ o
s7Fe I 11
~ CH3
~l ~ o
[1581
~0~5~)3~
- llL -
MIRAGE imagin~ compounds include those that are
generally used in nuclear medicine and are massive in
a recoil sense. When a Mosshauer absorber atom is
bound to a massive compound the effective mass of the
atom becomes the mass of the compound; therefor, the
recoil energy is not transferred to the Mossbauer
atom, and resonant recoilless absorption wAich is the
Mossbauer phenomenon occurs. This effect is
d~scussed in th~ Theoretical Sectio~. E~amples of
massive imaging compounds include the colloids
described in the Image Scanning Section where the
: radioactive atoms are replaced with Mossbauer
absorber atoms having a low internal conversion
coefficient or inorganic or organic molecules
possessing Mossbauer absorber atoms having a low
internal conversion coefficien~ where the substitute
atoms or molecule~ form the same type of bondinq as
the substituted radioactive atoms. Mossbauer
compound, l~Au colloidal gold and antimony 121
sulfide colloid are e~amples of this type of imaqing
- compound.
Furthermore, MIRAGE compounds for diaqnosis and
; therapy, in add~tion to the compounds described in
the Structure and E~emplary Material Sections, are
compounds containing Mos~bauer ab~orber atom(s) and
are m~ssive in a recoil sonse or are compounds
containing ~ossbauer absorber atoms which become
incorporated into th~ biological media aJ part of a
3~ mn~si~e compound which includes polymer molecules
such a~ proteins or crystalline structures such a~
bone.
The inherently massive compounds are organic or
i~organic polymers, colloid~, gelatin and de~tran
protected colloids, water insoluble macroaggreqates
3~3
- 112 -
or crystals or combinations thereof which co~ta.n
Mossbauer absorber atoms which are covalently or
ionically bound to these carrier molecules or esist
in a metallic, inorganic, or organic form as
occlusions or inclusions in these carrier molecules.
Polymer MI~AGE p~armaceuticals include proteins
labeled with Mossbau~r absor~er atoms such a~ ~7Fe
hemoglobin, l27I and l2~I labeled thyrotine,
~Sn, ~2lsb 125T~ 7~Ge, 12~ I,
12~ I, and 201 Hg labeled albumin and organic
and inorganic polymers of th~ size range of
appro3imately 5-50nm with Mossbauer absorbar atoms
bound covalently, by chelation, by coordination, or
electrostatically. Esamples include dibutyltin(ll9)
dimethylacrylate, ruthenium(99) b~sbipyridine poly
4-vinyl-pyridine, poly~bis bipyridine osmium(l~9) bis
~inylpyridine], s~Fe polyvinyl-ferrocene,
sulfonated polystyrene and ~afion and polymers
containing ethylenediaminetstra acetate and organo
silane-styrene sulfonate copolymeræ containinq
trapped cations of Mossbauer absorber atom~ includin~
those cations of the lanthenide, actinide and
tYansition metals.
The colloids include carbo~yl, sulphate,
phosphate, hydroside, and sulfide colloids containing
Mossbauer absorber atoms esclusively with the
appropriate counter ion(s). Esamples are
a~timony 121 sulfide colloid and l~Au colloidal
gold. Or, the colloids contain Mossbauer absorber
atoms in motallic, inorganic, or organic ~orm a~
inclusions and occlusions. Carrier colloids of this
type include carbosyl, sulphate, phosphate,
hydro~ide, and sulfide colloids and golatin and
de~tran protected colloids and micelle~. Specific
e~amples are Tc sulfur colloid, chromic phosphate
,
.; ~ .
~ .
.. ,~, . ..... .
03~t3
- 113 -
colloid, antimony sulfide colloid and de~tran and
gelatin protected colloidals, yttrium hydro~ide and
colloidal gold, containing inclusions or occlusions
of cations o~ ~ossbauer absorber atoms including
those cations of the lanthanide, actinide, and
- transition metals. Micelles include soaps and carry
organic compounds containing Mossbauer absorber atoms
suc~ as benzene labeled with l~Ts or l~Sn.
Water insoluble macroagqregates include 5~Fe
ferric hydroside and ferric hydro2ide macroag~regate
containing occlusions and inclusions includinq the
aforementioned cations. Cry~tals include water
insoluble microprecipitates of the approsimate size
range o~ 5-SOnm of cations or anions of Mossbauer
absorber atom~ such a8 la~I- and ~2~I ~
AgI or silver halide micropricipitates containing
Mossbauer absorber atoms in metall~c, inorganic, or
organic form a~ inclusions or occlusion~ in the
cry~tal includ~nq all of the aforementioned cations
of the lanthanidas, actinides, and transition metals,
and metallic and inorganic form~ of these isotope~.
Polymer compounds are prepared by attachinq
Mossbauer absorbcr atom~ or organic funct~onalit$es
containing Mossbauer absorber atoms to an organic
polymer carr$er by using the type of reactions
de~cribed in the General Synthet$c Pathways and
Esomplary Materials Section~, or those types of
react$ons are used to attach Mossbauer a~orber atom~
to monomer~ which are polymorized to produce
particles of tho ap~ro~imate sizo range of 5-50nm by
reactions generally known to ons skilled in the art.
For the cases whero the ~ossbauer abJorber atoms are
h~ld by cholation, coord$nate, or electrostatic
bonding, the atoms are e~changed into the polymer
~Q~5~ 3
- 114 -
backbone by reactions generally known to one skilled
in the art.
MIRAGE compounds which are inorganic polymers or
colloids, or micelles or water insoluble
macroaggragates or crystals or combinations thereof
and consist of Mossbauer absorber atoms or
functionalities containing Mossbauer absorber atoms
and counterions or contain inclusions or occlusions
of Mossbauer absorber atoms are prepared by preparing
the Mossbauer atoms or functionalities containing
Mossbauer absorber atoms and the other starting
reagents of the carrier compounds in the proper
physical form and by allowing them to form
condensation nuclei and grow in solution and by
isolating the product by filtration of evaporation of
ths solvent using reactions and techniques generally
known to one sk~lled in the art.
For e~ample, sodium thiosulfate i~ treated with
- HCl and technicium pertechnitate to give Tc sulfur
colloid. And, gol~ colloid i~ prepared b~ reducing a
solution of gold chloride with ascorbic acid or by
hoating gold chloride with an alkaline glucose
solution in the presence of gelatin. The product in
each case can be obtained by removing the solvent by
vacuum distillation.
Additional MIRAGE compound~ for dlagnosis and
therapy include those compound~ which contain
Mo~sbauer ab~orber atom~ which ~ecome incorporated
into blological molecule~ which are ma~sive in a
recoil s~n3e followinq admini~tration of the
compound~. Such compounds whlch contain Mossbauer
atoms in a form to permit incorporation into protein~
include water soluble ionic compounds containing a
Mossbauer absorber atom(s), a~ the cation or anion
~uch as those whlch dissolve in wator to release
, ~,
. ~:
.. ,~, .
, ! , . . .. .
1 ' ' ' .
353
sJFe3~ which is incorporated into hemeproteins
and l2,I- or l2~I- which is incorporated
into thyroid compounds. Mossbauer atoms which can be
incorporated into bone as occlusions and inclusions
include inorganic and metallic forms of ~g,
L5~Gd l~Gd ~Gd, l6lDy, l6~Dy,
a~d l~9Sm. ~he corresponding MI~AGE
pharmaceuticals are water soluble ionic compounds,
colloids, crystals, or macroaggregates containins
bon~ seeking Mossbauer absorber atoms in ionic ~orm
or the MIRAGE pharmaceuticals are carrier compounds
such as colloids, crystals, or macroaggregates
po~sessing bone seeking Mossbauer absorber atoms in
an inorçanic or metallic form aa occlusions or
inclusions. These compounds are prepared as
described previou~ly.
.
PREpAR~3~5~ELA~ RUIE~ F AD~U315~R2~Q~
MIRAGE p~armaceutical~ alone or combined wlth
carrier mol~cule~ can be administered orally, aa
~prays, intramuscularly, intraveneow ly, or br
subcutaneous, intra-artlcular, or intra-arterial
in~ection.
Medicinal formulation~ which contaln one or more
MIRAGE compounds as the active compound can ~e
prepared by mising the MIRAGE phsrmaceutical~) with
ono or more pharmacologically accsptable escipients
or dlluents, such a~, fo~ esample, flllers,
emulsifiers, lubricant~, fla~or corrocting agents,
dyestuff~ or buffer substance~, and converttng the
miYture into a ~uitable galenic formulation form,
auch a~, for esample, tabletJ, dragee~, capsule~ or a
solution or su~pension suitable for parenteral
ad~inistration. ~ample~ of escipients or diluents
which may be mentioned are tragacanth, lactose, talc,
~,
.,
2 1:)~5(~3~3
- 116 --
agar-agar, polyglycols, ethanol and watPr.
Suspensions or solution in water, de~trose, saline,
or dimethyl sulo~ide can preferably be used ~or
parenteral administration.
Also, MIRAGE pharmaceuticals can be prepared as
sterile lyophilized powder to which a sterile solvent
su~h as water or d~methylsulfoxide is added. MIRAGE
pharmaceuticals are also prepared a~ a sterile
lyophilized powder containing deoYycholate to effect
a colloidal dispersion of insoluble MIRAGE
pharmaceutical. These preparation~ are administered
a~ injectables including intramuscular and
intravenous administration.
Topical MIRAGE pharmaceuticals can be prepared
as a cream, lotion, gel, ointment, and spray.
It is also possible to administer the active
compounds as such without e~cipients or diluents, in
a suitable Çorm, for e~ample in cap~ules.
MIRAGE pharmaceuticals can be packaged employing
the u~ual sorts of precautlons which the pharma~ist
ganerally observes. For e~ample, the preparations
may be packaged in light protect~ng vials and may ~e
refrigerated if nece~sary.
; 25 ~ EA8A~S
The overall operation of the sy~tem may be
esempliied by the coo~/Fes~ Mossbauer pair a~
follow~: the radioactive source in the form of a
thln film of material such a~ stainle~ steel,
co~per, or palladium into whlch radioactive Co-57 has
be~n allowed to dlffuse to provide a beam of highly
homogeneous photons having an average energy o~
14.4 XaY. The homogeneity, or line width ~E is
4.5~10 9 eV so that ~E~E is less than 10 12. A
.
'
',;
':
.
2~ 3
- 117 -
filter selects the 14.4 KeV photon from the other two
photons of dif f erent energy.
The source is mounted on an accurately
controlled mass drive, which shifts the energy or
~reguency of the photon ~y the Doppler effect. A
wide variety of commercially available velocity
drive~ esist. A velocity of lmm~sec corresponds to
a~ energy chanqe of 4.8~10 8 eV or more than ten
line widths. T~e arrangement 100 shown in Fig. 1 is
one in which the source 50 is mounted on a cone 62 of
a speaker 60 and the speaker is driven so that the
relative position of the speaker coil increases and
decreases linearly with time (symmetric triangular
wave form) at approsimately 5 Hz. Since the
displacement of the speaker coil is quite closely
proportional to the input voltage, it is necessary to
provide a ramp voltage in order to produce a linear
volocity. This i~ accomplished by a triangular
wave. A function generator S~ i~ employed to produce
an accurate, lo~ frequency t~iangular voltage. This
voltage is applied to the speaker 60 through a power
ampli~er 56. In practice, it i8 necessary to employ
considQrable negative feedback to produce an accurate
linear velocity. This is accomplished hy coupling a
~ocond (or u~ing a double voice coil 64) speaker 66
to tha drive speaker 60 with a rigid rod 52, and
~rovtding the error signal ~rom the second speaker
(~onitored by o~c~lloscope 5h) to the amplifier 56
through the integrator 68 as shown schematically in
Flg. 1. Tho source 50 i~ mounted on the rod
connectinq the two speaker~.
S~nca the source e~ecute~ two velocity
e~curs$on~, ono at positive and ono at nogative
valocit~es, a ~ynchronized shutter 70 can be used to
block radiation during the nonresonant e~cursion.
: .
r~
i'':' .
2()~3503~
- ~18 -
In addition to tuning the energy via a Doppler
shift, th~ emission energy of a Mossbauer source is
continuously tunable by driving it ultrasonically. A
Mossbauer source can be adhered to a piezo-electric
transducer such as a quartz or barium titanate
transducer and driven at ultrasonic frequenciPs to
produce an ininite number of side bands in the
emitted radiation which are removed from the central,
unshifted line by an integer multiple of the
ultrasonic frequency and the relative amplitude~ of
the side bands can be varied by varying the power
applied to the transducer. The ultrasonic Mossbauer
side bands can serve as a variable-frequency energy
source. The ultrasonic power i5 selected so that
essentially only the first side bands have
appreciable intensity and the ultrasonic drivinq
frequency i~ chosen so that the emission sidebands
are of the desired energy. A variable-frequency
ultrasonic Mossbauer spectrometer based on this
principle i~ described by J. Mlshorr and D.I. ~ole~,
~ , Irwin J. Gruverman,
Edltor, Vol. 4, (196a) pp. 13-35, incorporated by
reference.
In one embodiment, ultrasonic tuning of the
g~mma ray source 202 is shown in Fig. 7 where a
~ource 204 of ultrasonic energy energizes the gamma
ray source 202 through an acoustic coupling media to
; produce e~ission side bands of energy which is
- tu~nble by changing th~ ultrasonic driving frequency.
!' 30 The source, or emitter of radiation, can also
~ include the techniques known to Mossbauer
; s~ectroscopy of narrowing the line width or absorbing
unwanted Mossbauer l~nes. In add~tion, unwanted
r~diation such as particle rad~ation can be absorbed
by a filter and wanted electromagnetic radiation can
~Q~
- 119 --
.
be separated from unwanted electromagnetic radiation
by addition of single frequency filter 80 shown in
Flg. 2. The filter 80, receives source 50 radiation
through an input collimator 82 and enters a
S diffraction crystal 84. Since the diffraction angle
can be calculated (Bragg equation n~2d sine), the
de~ired frequency is s~lected by placement of a
s~cond output collimator 86 and the selection of a
crystal having a~ appropriate intranuclear layer
distanc2 (d~.
rn addition to the above-mentioned photon
sources, the photon emitters of Table 7 are us~ful in
- conjunction with the correspondingly listed absorbers
incorporated as pharmaceutical agents.
Fluorescence, or nuclear emissions of the tissue
components e~cited at the Mossbauer frequency can ba
observed from the target area. The dynamic range
~signal-to-noise~ can bo enhanced by vi~wing the
sub~ect 90 shown in Fiq. 1 off-a~i~ from ths i~cident
radiation from the source, thereby eliminating the
background level from the source. Off-asis v$ewing
i~ pos~ible due to the continuum of angles of
f luorescent emission of the target tis~ue component
at the Mossbauer frequency. Moreover, the frequency
of the fluoreJcence will coincide with the ~requency
of the source due to the nrrrow ~pectrum of the
~ossbauer r~onance. Also, due to tho f inite half
life of tho e~cited state, fluore~cence can be
dl~criminated from esciting radiation by timinq th~
arrival of the signals.
- Furthermoro, fluore~cenc~ can b~ continuouslY
monitored b~ sonsor~ such as 92 shown in Fig. 1 to
qive a ch~racteristic plot o~ the treatment
effectivenes~. A spa~ially distributed srstem o~
; 35 multiple detectors such a~ proportional counters or
:
.
, . .
~,,,,~,
~0~503~
- 120 -
scintilation detectors, or lithium drifted silicon
and germanium detectors where each detector has a
collimator at the aperture for the entry of photons
can localize the source o~ fluorescence. Photons
must travel in a straight line, and each collimator
will only parmit photons propagating parallel to its
asis to enter its dotector. Thus, the orientation of
the asis of each detector's collimator rolative to
the treatment f~eld assigns a propagation direction
for source gamma rays called a ray path. The
direction that gamma rays ars beinq administered
assigns another, and signals from multiple detectors
at oth~r orientations assiqn other ray paths. The
intersection of two or more ray paths gives the
location of the fluorescent source of gamma rays. In
addition to the location of the source o~
fluorescence wh~ch i tho slte of treatment, the
intensity at the detectors giv~ the intensity of
treatment. A control signal can be derivad from the
fluorescence, and combined or processed ~y
proce~sor 94 of F~g. 1 according to tho orientation
of detectors whlch record signal directlon and the
- i~tensity o~ the recorded 3ignals to continuously
control the source of fluorescencQ to optimize the
troatment. And, the apparatus could al~o be combined
wlth imaging equipmen~ such a~ computed tomography,
magnetic re~onance imaging, and ultra~ound imaging
wh~ch could be used to determine the sp~tlal location
of tho selected tl~ue to provi~e ths coordinates to
b~ u~ed with the fluore~cent slgnal to control tho
~lte of troatment.
r'' ,I~ an alternate do~ign, tho imposed magnetic
fiold may be u~ed to produco an enorgy transition for
absorption of the radiation without the necessity of
a doppler shift of the gamma source. The requirement
3~3
- 121 -
of a magnetic ~ield of predetermined magnitude
provided by current adjustment 108 of Fig. 2 and
direction can be accomplished by using Helmholtz
coils or surface coils discussed below. An e~emplary
apparatus is shown in Fig. 2 which uses Helmholtz
coils 102, 104 where the patient 90 is oriented along
the z asis of the coils. A uniform field of
specified spatial dimensions can be created by
varyiny the radius, a, and ths distance, z, between
the coils. The field is saddle shaped with the field
at the saddle point beinq uniform and strongly
divergent rom uniform immediately adjacent to the
saddlepoint. The equation for the field of the coils
with the current in the same direction is given as
follows:
; ~_/ NI ~ --)~/ (2,
Helmholtz coils can bo placed in a longitudinal
configuration relative to the patient as shown in
Fig. 2 and transverse to tha patient. A system of
such Helmholtz coils are used as described below to
efect the field characterstics necessary to cause
selective absorption of Mossbauer radiatisn in the
desired location via the mentioned magnetic hyperfine
splitting and polarization effects.
Salectivity in treatment is achieved by imposing
a magnetic field gradient of sufficiant steepness
.. which e~ploits the dependence of re~onance energy on
field strength so that resonant ab80rption can be
localized to specific d$mensions (such as that of a
; tumor) while maintaining nonre~onant, and there~ore
nonabsorptive, conditions in the surrounding
nonselected tissue ~t the energy of gamma rays
~o~o~
- 12~ -
imparted to the tissue. To achieve this situation,
the field gradient (field strength difference) must
be such that the induced resonant eneryy difference
across the selected space is one line width of the
e~citing gamma rays.
- The parameters and calculations involved are
-- discussed in the Theoretical Section, below.
In one embodiment, a gradient field is produced
by the Helmholtz coils of Fig. 2 where the steepest
L0 gradient is produced when the induced field from each
coil opposes that o~ the other. The field gradient
produced by such configuration of Helmholtz coils is
given as follows:
~ = ~f/I3Z~
2 ~ ( / ~ z l)S/~ (3)
where Zo is the normalized source coordinate.
Equation 3 and equations for current distributions to
; produce desired field gradients appears in U.S.
Patent 4,617,516 and its references which are
incorporated by reference.
In addition, a magnetic field of high field
strength gradient and/or with field lines which
change from linear to linear at a 90 degree
(perpendicular) angle over a small spatial
displacement is produced by Helmholt2 surface coils
such a~ 110, 112, 114, and 132, 133 u~ed in magnetic
re~onance imaging which appear in Flgs. 3 and 4,
respectively, and which appear in Nature, Vol. 287
(1980) p. 736 incorporated by refarence. Such
surface coils can typically achieve field strength
gradients of 2000 gauss per centimeter. The
corresponding magnetic field lines are shown in
Flgs. 3A and 4A, respectively, where a saddlepoint is
shown at 122. Moreover, the gradient can ~e
2~50~3
123 -
slgnificantly increased in the case where a very high
coil current is sustained for a limited tim~ to
prevent thermal damage to the coils. Surface coils
can be used singularly or in combination to e~ec~
tho de~ired field configuration and ield gradient.
And, the coil dimensions, num~er o~ turns, current in
each coil, and the relatlve po~itlon o~ the coils can
b~ ad~usted to achievs the desired field. The
- conftguration of Figs. 3, 4, 5 and 6 can be used with
the apparatu~ of Flg~. 1 and 2 to achieve
localizatlon of the Mossbauer effect ~y esploiting
the dspendence for resonance o~ tho polarization and
propagation d~rectlon of the gamma ray ~or Mossbauer
absorber nuclei aligned by the pre~ence of a magnetic
f~eld as described in the Theoretlcal Section, below.
For esample, the gamma ray could follow radlally
dlrected f t eld llnes into the body and cut asial
fleld lines deep in the body at the location of the
ta~get ti~ue. A~ esplain~d in the Theoretical
- 20 Section, when the gamma ray ha~ the proper energy,
polarlzatlon and propagatlon dlrectlon, the nuclear
tran~ition~ of the Mossbauer atom~ in tho pre~ence of
tho p~rallel fleld llne~ are nonresonant with the
ad~lni~tered gamma ray~ whtle t~ose 1~ the presence
o~ the perp~ndlcular fleld l~ne~ are re~onant for the
a~ ~ 0 tran~ltion.
Combinatton~ of Holmholt2 coil pJir~ could
achle~e ~electlvity by eYploitlng tho condltion~ for
r-sonance of g~mma ray en~rgy, polarizatlon and
~ropagation dlrection. For esample, tho pair of
Holmholtz colls 102, 104 of Flg. 2 can be used to
produce a saddle shaped field wh~ra a uniform field
parallel to tho body asis i~ producod at the saddlo
point. As described or a structure of Fig. 6 having
co~ls 152, 154, lS6, 15B, 160 and 162, the Volume 164
5(~3g
- 124 -
o~ the field saddle point can be made less than
13~3. Furthermore, the tran~verse component of the
magnetic field of a sur~ace coil is zero along it~
asis, and, the a~ial ~ield i~ zsro in the equidistant
S planQ o~ two matched Helmholtz surface coils with
opposite currents. The intersection of the a~is oÇ
the coils with the eguidistant plane constitutes the
saddle point of these coils.
Sp~tial treatment selectiYitr can be achieved at
the lmm3 volums le~el by applying surface coils in
a configuration of Fig. 2 such that t~e plane~ of the
surface coils are parallel to each other and
; perpendicular to the planes of the Helmholtz
coils 102, 104 and such that the sad~le point of th2
former superimposes that of the latter. Tre~tment i~
carried out such that the gamma rays propagate along
- the a~is o~ the two surface coil~ 112 and 114 or
alonq a radlal field line in the equidi~tant plane of
the t~o surfac~ coils 116 and 118. rn both c~ses,
the gamma ray~ would e~counter parallel aligned
nuclei e~cept at the intercept of the saddle points
whore the rays would ancounter nuclei al$gned
t~nsvQrsely to the g~mma rays' propagation
dlrQction, and selective absorption will occur for
the o~ O lin~ by the proco~ described in the
Tneo~ot~cal Section.
An alt~ration of this scheme is to uso tuo pairs
body Helmholtz coil~ ~uch a~ tho~e ~hown in
~. 20 Each pair i~ matched, and the current is in
opposite dlrcc~ions for one pair and is in the same
diroction or tho other pair. The fiel~ produced by
the former pair is greater than that produced by the
latter. Treatment i8 performed by administering the
gam~a ray~ in tho radial direction in the equ~distant
plaae perpendicular to the asis of all four coils.
- 125 -
S~1QCtiYitY is achieved by the polarization and
en~r~y mechani~m for tho ~m = O transition as
described in tho Theoretical Section because the
field is predominantly radial escept where th~ gamma
ray intersects the coils' ases whore the fiald is
predominantly asial. This is becau~e the field
contributed by opposing coils i~ rad~al with zoro
longitudinal component at th~ 8 point; wherea~, tho
field of the coil~ with the current in tho same
d~rection produce a large longitud~nal com~onent at
this point.
The ase3 of coils used to produce a maqnetic
; field d~scussed so ar coincide with an asis which
pa~se~ through the patient. Another configuration o~
coils to produce a ~radient ield i~ two esternal
coils whoso common asis doQs not intersect the body
but is aligned p~rallel to thQ asis through the body
~elected a~ th~ gradient asi~. With such a coil
arrangement ao d~monstrated in Flg. 3, the depth at
which the re~onanco cond$tions occur can be solected
! by controlling tho ratio of th~ currents in tha two
coil~.
The C0$13 di~cussed thu~ far are Helmholtz
coils, shown in Flg. 4, which produce a ield a~
ahown in Flg. 4~. In Flg. 4A, the 1UY pattern of
tb- surace co$1 132 i~ indicated by tho line~ 134,
~n~ the fiola profile (i.e. line~ of constant
inten~ity) are indicated by lino~ 136, 138, an~ 140.
Th~ fiol~ i~ rotatlonally ~ym~otric with roJpeCt
to tho asl~ of tho coll 132, but tho component of tho
fi-ld directed p-rpendicularly to tho as$s of the
coil doos not eshlbit the same rotat~onal symmotry.
For all points off as$s, there i~ a non-zero
tran~verse comPonent. Thus, tk~ surface~ of con~tant
transvorse f~old (whose trace~ in the plane of
~3~35~3a~3
-- 126 --
i
Fig. ~A correspond to lines such as 136 to 140) ar*
of somewhat distort~d spherical shape. The location
of the selected tissue is b~tween lines 142 and 144.
In practical terms ~ it is appropriate to consider the
oparation in relation to layers of fi~ite thickness
corresponding to a resonant condition along tha field
; gradient of on~ linewidth; two such layars are
indicated at 146 and 148 in Fig. 4A.
A surface coil shown in Fig. 5 i3 wound ia a
- 10 fashion and geometry which departs from that o~ a
- Helmholtz coil where the f~eld produced, ~ig. 5A, by
the former is considerably di~ferent from the
latter. In Fig. S, a surface coil is shown which has
several turns la2, and 183 which enclose eac~ other
at least partially and which aro arranged at
differant geometrical points. ~ach turn preferrably
comprises substantially a single conductor section or
sev~ral conductor sections arranqed in a group, the
current flows boing opposite to each other in
~utually ad~acent turns. The fiola produced br this
coil i~ shown as Flq. 5A. In Flg. SA, the field is
~hown in a pl~ne perpendicular to the plane of the
coil with the Y a~is beinq the a~s of the coils.
The location coordinateJ are i3 arbitrary units and
tho lines of constant field strength are given w$th
the relative strangth ratio~ entered alonq the
r-~ective curvoR. Such a coil produces a steep
~leld grad~e~t ~n strenqth an~ direction at depths
fro~ the surface which i~ u~ful to realized
solectivitr by ~olarization and energy mechanisma
di~cu~sed in the Thoorstical Soction.
rn a pre~orr0d method where fiold~ are u~ed to
achieve selectivlty, troatment is carrlsd out so that
the prop~gatlon direction of tho gamma ray i~ along
the steepest p~rt of the field gradient with rsgard
~5~3~S3
- 127 -
to strength and/or direction such that no volume
containing nonselected tissue along the ray path
satisfies the resonance conditions for absorption of
the gamma rays administered to the selected tissue.
S In addition, the apparatus possess a means to
selectively create absorption side bands of the
Mossbauer absorber nuclei of the selected tissue.
Absorption side bands of Mossbauer absorber 7llclei
can be produced by producing ultrasonic motion c. the
nuclei along the direction of the incident re~, aant
^` gamma rays. The shift in energy and the amplit~des
of the sidebands can be controlled by controllini, the
ultrasonic driving ~requency and the ultr-~o~ll
power, respectively, as described by J. Mishor~ and
D.I. Bolef, Mo$Sbauer Effect Met~Q~olQ~y, Irw ~ J.
Gruverman, Editor, Vol. 4, (19~8), pp. ~-35,
incorporated by reference.
Selectivity is achieved by administer :g a
narrow ultrasonic beam which intersects the
administered gamma ray beam at the selected issue
site. The narrow ultrasonic beam is collimat~d or
focused.
The beam from an ultrasonic transducer is
collimated to a depth of D2/~ where D is the
transducer width and ~ is the wavelength of the
ultrasonic wave. Thus, or producing a collimated
ultrasonic beam to produce absorption side bands at a
dapth z, the transducer size is given by equation 4.
~ Dop _ z~ (4)
Focused beams are produced by the use of an acoustic
lens or by dynamic ~ocusinq through electronically
controlled transducer arrays. An acoustic lens is
generally made of a plastic material which has an
~()OS039
28 --
:.:
acoustic propagation velocity greater than that of
water: thus, the refractive indes is less than one,
and the lens is positive converging. For such a lens
of spherical curvature, the field amplitude is the
Fourier transÇormer of the source distribution at a
depth of Z = f, the focal length. This results in an
effective lateral beam width at the focal plane of
~f~D. The velocity of sound in soft tissue i5
1.5 x 105 cm~sec and the relationship between
velocity, v, wavelength,~, and frequency, W, is as
follows:
~ = ~ ~ (5)
Thus, the width at a focal length depth of 10 cm of a
10 MHz beam produced by a transducer of 1 cm width is
.15 cm. The same beam width relationship is achieved
by electronically controlling a transducer array.
The output intensity and temporal relationship of
acoustic emission of the array elements are
controlled to produce interference effects to produce
a focused ultrasonic baam. Rectangular annular ring,
concentric rin~, and Theta arrays to produced
electronically focused ultrasonic beams in addition
to acoustic lenses and collimated transducers to
produce narrow directed ultra~onic beams are
d~8cribed in ~ , Albert
Macovsik, (1983), pp 173-223, lncorporated by
reference.
Treatment i~ per~ormed by dlrecting the
ultrasonic beam at the selected tis~ue to e~cite a
component of ultrasonic motion of the Mossbauer
absorber nuclei in the direction of the beam of the
administered gamma rays which intersects the
ultrasonic beam in the selected tissue. The
..
:
3~3
- 129 -
u}trasonic beam creates ab~orption side bands ~or
Mossbauer nuclei in the selected tissue of energy
shift equal to the ultrasonic driving frequency~ To
achieve selectivity the driving freguency is varied
to shift the side bands to an ener~y which is
nonresonant with the nonselected tissue through which
the gamma rays of energy resonant with the side bands
travel to the selected tissue site. And, the
amplitude of the escited absorption side band of the
Mossbauer absorber nuclei of the selected tissue is
ma~imized by controlliny the power of the ultrasonic
heam.
In one embodiment, ultrasonic tuning of the
gamma ray source 202 is shown in Flg. 7. A
source 204 of ultrasonic enerqy energizes the ~amma
ray source 202 throu~h an acoustic coupling media.
Alternatively, or in combination, a beam 206 af
acoustic energy is provided by a source 208 to cause
the Mossbauer ab~orber atoms to ab~orb the gamma rays
at a target area common to both the path 212 of the
gamma rays and the beam 206 of acoustic energy.
Treatmant can be controlled by a microprocessor
which receivea digitized input from peripheral
sensors which follow patient movement and
di~placement; velocity and acceleration o f the mass
drive; shutter po~ition; tho magnetic field strength
an~ gradients; the frequency and voltage amplitude o~
tho source ultrasonic transducer; tho ad~orber side
band producing ultrasonic boam~ 8 diroction,
froquency, and inten~ity; a~d Mossbauer
. fluore~cenco. Source actlvities of the order of
103 ci are possible so that troatment can occur
over m~croseconds. Thus, precise treatment can be
efected by electronic control in the pre~ence of
patient movement which occurs over times many orders
~S03~3
- 130 -
of magnitude greater than the processing times of
r high speed control systems.
~DLI~3Q~ *P~Sa3ION~
MIRAGE drugs and therapy hav~ many diverse
applications in addition to the treatment of cancer.
For esample, MIRAGE compounds can be used for imasing
.~ and for treatment of any disorder which in~ol~es the
eradication of calls which are implicated in the
dlsorder. Dlsorders of the latter type include
arthritis, autoimmune disease, t~ssue transplantation
rejection, atherosclerosis, and AIDS.
IM~GE ~ÇBE~
Radionucleotides, which ha~e short hal~ lives,
on the order of hours, and which are gamma-emitting
i~otopes, are u~ed in scintiscans to gain dlagnostic
information based on the phy~iological properties of
the pathological proces~. These propert$e~ include
dlfferential uptake, concentratlon, or escretion of
the radionucleotide by normal ~ersus diseaYed
t~ssue. For esample, hopatlc sclntiscans are
p~rformed with gamma-emitting i~otopes that are
estracted selectively by the liver, ~ollowed by
esternal rad~ation scanning of the upper abdomen.
Sh~re are baaically three type~ of l~er scan~: the
colloidal scan, wh~ch depends on uptake o labelled
colloid by gup~fer cells, where l~7Au colloidal
gold or ~9m~c sulfur colloid i~ mo~t commonly
uaod; thc HIDA or PIPIDA ~can~ (77mTc-labelled
N-aub~tituted imlnoacetic acl~s) in which the dye i~
. 30 taken up and escreted by hepatocyte~, and tho gallium
scan, in whlch the radlonuclido ~7Ga i5
concentrated in neoplastic or inflammatory cells to a
greater degree than in hepatocrtes. Honce, a
3~
- 131 -
hepatoma or liver abscess will produce an are2 of
- reduced uptake or Uhole~ using colloid or HIDA or
PIPIDA scans, but there will be an area of i~creased
uptake or ~hot spot~ with a gallium scanO The
gallium scan is also help~ul in diagnosinq neoplastic
infiltration in the patient with cirrhosis, since the
tumor will show increased upta~e, while fibrous bands
will show decreased uptak2. Another major
application o~ HIDA or PIPIDA liver scans is in the
diagnosis o~ acute cholecy3titis, where failure of
the nuclide to enter the gall bladder is considered
e~idence of cystic duct or common bile duct
obstruction. The normal physiology involved is the
uptake of these compounds by the hepatocytes followed
by escretion into the biliary canaliculi and
concentration in the gall bladdar.
All Mossbauer isotope~ are gamma emitters
following absorpt~on of the s~me energ~ qa~ma photon,
and mo~t are stable isotopes; therefore, they can be
u~ed in sc$ntiscans. MIRA OE imaging compounds are
described in the Macromolecular MIRAOE Pharmaceutical
Section. As i~ ths caJe of radionuclides,
information can be g~ined based on differentlal
uptake, escretion, or concentration a~ a consequence
o~ tho phyJiology of the patholoqical ~roces~. But,
Mos~bauer ~cintl~can~ a~o provi~e the ability to
d~agnohe dlsea~e proce~se~ and to ~-lectively i~ge
dif~erent tls~ue~ ba~ed on the phonomenon of the
differential r~onance ~requency of the absorber
i~otope in dlf~erent tlJ~ue environments via
~ mechanism~ dlscu~ed uDder selectivity in tho
; Thooretical Soction. Esciting the ab~orber i~otope
or iJo~opea b~ causing a solected energy emission
from tho source along one a~is and simultaneously
scanning with convent~onal Scintiscan in~trumentation
;~0~0~3
- 132 -
- along an axis different from th~ former a~is produces
a Mossbauer Isotopic 2esonance Absorption o~ Gamma
Emission (MIRAGE3 scintiscan. Due to attenuation of
the esc~ting beam aa a funotion of distance along the
source asis, a correction algorithm ha~ to be used to
process the data to produc~ an im~g~ of the actual
distribution of the Mossbauer isotope or isotopes in
the tissue.
AR~E~3~S- AU~
10T~A~&pLA~a3~ON RE~E~I~ DISEaS~
A success~ul treatment for rheumatoid arthritis
is the induction of necrosis of synov~al cells o~
afflicted joints~ For e~ample, intra-articular
radioactive synovectomy using the radionucleotide
~Dy coupled with the massive inert carrier,
forric hydroside macroaggregate, ha~ been shown by
Sledqe, et. al. ~Sledge, Clement, B., Clinical
Orthopedic~ and Related Research, No. 182,
January-February 1984, p~. 37-40, incorporated by
reference) to bo an effective mean~ of roducing
inflamation, effu~ion and paln in patients with
rheu~atoid arthritis.
MIRA OE therapy provides selectlve cellular
nocro~is and intra-art~cular MI~A OE synovectomy can
b~ sub~tituted for intra-artlcular radio~ctlve
~ynovectomy to give the ~ame thorapeutic effect, and
by substitutlng stable Mossbauer ab~orber i~otop~s
for radioactiv~ Dy in the ~ynovectomy
treatm~nt, sy~temic radiatlon esposure from leakage
i~ avoidQd.
F~rrlc hydro~ide macroagqregate is massive in a
rocoil sen~e an~ it an other ma~sivo inert carriers
of 108 d~ltons or greater whlch wore deJcribed
previously would be effective in pormit~ing the
~0~ 3~3
- 1~3 -
Mossbauer effect to occur. MIRA OE therapy is
performed in this case with the preYiously mentioned
massive inert carrier molecules containing stable
Mossbauer atoms such as lDy, ~6JDy~ ~Fa
and ll~Sn in matallic, inorganic or organic form
which are administered by iatra-articular injection,
and r~sonant Mossbauar radiatlon i~ administered to
the jointsO
Other disease~ which can b~ cu~ed b~ inducing
necrosis of specific cell line~ include autoimmune
dlsease~ and transplantation rojection diseass which
includes graft versus host and host versu~ graft.
The cellular mediators for both of these diseaseY are
lymphocytes. ~he responsible cell line~ can be
eradicated by synthesizing hybrid pharmaceuticals
- consisting of a protein and a MIRAOE pharmaceutical
where the M~RAGE pharmaceutical include~ one of those
fonmed by derivatizing a D~A binding molecule of
~able 6 with a Mossbauer ab~orber atom of Table 7 as
d~scribed i~ the Genaral Synthetic Pathways and
Esemplary Materials Sections, a~d the protein
includes a monoclonal ant$body, the protein and
MIRAGE pharmaceutical are attached by a covalent bond
such a~ a disulfide, amide, e~ter, ether, amino, or
c~rbon-carbon bon~ which is formed by u~in~ eslsting
fu~ctional groups or by placinq functlonal groups on
tho protein and MIRAGE pharmaceu~lcal such aJ
c~rbo~yl, amino, sulfide, halogen, or carbonyl and
condensing tho two entities together by mothods
gonerally k~own to one skilled in tho art. The
~rotein blnds to surfaca of the target coll in a
hlghly speci~ic manner. A monoclonal antibody to an
antigen on the cell surface or a hor~one whlch binds
to a receptor on the cell surface coul~ serve a~ the
protein delivery molecule. The binding protein and
2~5g3~
ths attached drug are internalized together and the
protein is degraded releasing the MIRAGE drug which
binds to a cellular target such as the cells' DNA.
The tissue is irradiated at the re~onant frequency of
the pharmaceutical molecule bound to the cellular
targetO The subsequently released Auger elec~rons
causes irreversible damage to the cell which is
elimiaated where the eliminatlon sarve~ a therapeutic
function.
MIR~E D8~G FO~
M~RAGE therapy can be used to eliminate the
cells responsible for atheromas and involved in
atherosclero~is.
- 15 The occlusion of arterie~ is the end result of
the atherosclerotic proce~ which involves the
following stages 1~ repeated i~jury which denudes the
vossel of endothelium, 2) deposition of platelets,
fibrin and lipids, 3) inward migration of smQoth
20 mu~cle c811s and fibroblasts and 4) recanalization.
~he cycle repeats unt~l vossel occlusion occurs.
Rocanalization at this point or lu~an enlargement at
a stage preceding occlusion require~ removal of
smooth muscle and fibroblast cells without damage to
those cells of the same type which make up the vessel
w~ll. Thl8 i8 possible, however, wlth MrRAGE drugs
whlch c~n klll cells whtch have i~cor~orated the dru~
br u~ing levols of radiation which pw e no threat to
he~lth. Solectlvity in thls c~o i~ b~sed on
s-lective uptJke which i~ po~ible based on the fact
that the s oth mu~cle cells and fibroblasts which
must b~ removed interface the blood directly. A
; protein MIRAGE drug conjugate molecule which does not
cross endothelium and binds to the surface of the
2 ~ 9
- 1~5 -
smooth muscle and ibroblasts and not e~dothelial
cells represents a selective drug because binding can
only occur with those cells which interace blood
directly. Specific binding proteins include
monoclonal a~tibodies to Platelet Derived Growth
Factor (~DGF) receptor. B~nding is followed by
internalization, degradation, and rclease o~ the drug
which binds to a susceptable b~ological target such
a~ D~A. Irradiation at the re~onant Mossbauer
absorption en~rgy [frequency] of the bou~d drug then
eliminates the occluding cells so that the vessel
become~ patent.
M~ A~DE~
MIRAGE therapy can be made sel~ctiv~ for the
d~sease AIDS where infected ~ cells are erad$cated as
a therapeutic funct~on.
Acquired immune deficiency syndrome (AIDS) has
spread esponentially and i8 predicted to reach
ep~demic proportlon~. A conservatlve e~tlmate of
U.S. virus a~tlbody po~itive ind~viduals i~ 106,
and the U.S. death rate in the near future based o~
this figure i~ 54,000 deaths per year whlch compare~
with 30,000 dGath~ per year due to breast cancer.
AIDS i~ a ~atal disease with no speci~ic treatment,
and deYelopment of a vaccine presents a tremendou~
challenge for whlch there i~ no ho~e for ~uccesa
earlier than 1990. Furthermore, tho de~elopment of
e~perim0~tal drug~ for tho treatment of AIDS haa so
f~r procee~ed via a strategy comparable to that
` 30 utllized to develop antiviral drug~ for viru~e~ Yuch
aa Herpe~. HIV, the causative agent of AIDS, behaves
vory differently from other human pathogenic vlru~e~
because i~ destroys the T cell segment o~ the immune
sy~tem whlch normally i5 reapons1ble for controlling
~o~
- 136 -
the elimination of a viral challenge. In fact, HIV
i~ unique as a retrovirus in that it is cytopathic.
Also, the biology of the virus is such that it can
elude th8 immune system during a latent phase and
then activate to produce virus at a tremendous rate
b~fore th~ host cell dies. This life cycle is a
consequenc~ of a transactivatin~ factor, tat III, and
trst a gon~ product unique to HIV. The later protein
controls the diferential splicing of the viral
~ossaqe at diSferent points in the v~rus life cycle.
Th~ comple~ in vivo ~ohavior of HIV, wh~ch i~
characterized by persistent infection in the human
host, may depend on the regulatory control of viral
RNA splicing and translation. With a capacity to
e~pres~ viral regulatory, but not ~tructural
proteins, H~Y infected cells may avoid the host
immune rasponse but would be a~le to actlvate virion
production qu$c~1y following additlonal viral or
cellular s~gnals. Inde~d, ono manife~tation of
latency ~oen in visna virus inf ection i~
characteriz~d by viral R~A synthesis without
subsequent virion assQmbly. Llkewi~e, HrV infected
but nono~pre~sing human T cells can be viably
m~inta~ned in long term culture, only to die when
virus production is induced by immunologic
st~mulation.
~ he cytopathic effect of HrV dlroctly correlates
~th th~ a unt of viral envelop protein synthQ~ized
ln infocted cells. ThU8, efficient HrV production
may r-qulre ra~id viral protein synthe~i3 and
a~sembly in the race between virion rs~easo and cell
desth. The presence o large a unt~ o~ tat III at
the tim0 of a trs-mediated splicin~ pattern switch to
the synthesis of genomic and envelop mRNAs may thus
fac~litate production of a very cytopathic virus.
)3"3
- 137 -
Antimetabolites and molecules which inhibit HIY
enzymes can only slow the relentless progress of this
disease which destroys the host~s immune system by a
T cell cytopathic life cycle. The viral message
5ssists in the host DNA and is replicated with the
host D~A. An infected cell represents a silent
harbinger poised to release i~fectious viral
particles following the proper cellular or viral
signals. A reasonable approach to curin~ AIDS in an
10infected individual is to destroy all such cells
beore the host~s immune system i5 inundated with
virus and irreversibly compromised. MIRAGE drugs
; represent agents which can selectively dlscriminate
and destroy HIV infected cells in the lat0nt stage.
15MIRAGE drug selectivity can derive from
selective uptake, a unique isomer shift, hyperfine
splitting, and~or activation to parmit binding to a
larse target which permits the Mossbauer phonomenon
to occur. The enzyme~ involved in the life cycle of
20the ~irus can bc used to activate a drug only in
cells harboring the virus. Activation results in the
selective deposition of Mossbauer radiant energy in
tha HIV infected cells using one of the mentioned
m~chanisms. B~ed on the present knowledge of the
25biochemistry of HIV, the esploitation of the
activation of a uni~ue chemical shlft is ~ensible.
ThG mechanism i~ is e~plained in tho Theoretical
, S~ction.
Activation which in~olves chanqes in the
30chemical environment at tho Mossbauer atom of an
intercalatinq MIRAGE drug can be e~ploited a~ a
m~thod to solectively eliminate Hrv infected cell~ in
tho latent stage. Tat I~I is the only protein known
to be e~pressed durin~ HIV latency. Thls protein is
35both a cytoplasmic and a nuclear protein of about
503~
- 1~8 -
14kd. ~IRAGE drugs to cure A DS are those that
intercalate and also bind tat III. The later
interaction must change the electronic environment at
the Mossbauer nucleus to create a unique chemical
shift. Intravenous and intrathecal administration of
such a drug followed by systemic irradiation at the
frequency of the created isomer shift will
s~lectively kill latent infected cells and interrupt
the infectious process.
~ =~
PR~c~ LOF R~D~A~Q~ EAEY
Ionizing radiation was found shortly after its
discovery to be capable of reducing the growth of
human tumors. Unfortunately the limitations of this
modality were d~scovered as patients developed
catastrophic late complications. The radiotherapist
must perform treatment such that the balance of thesa
opposing ends i~ in favor of tumor ablation. ~he
total story of the cellular mechanisms involved
rema~ns elusive; however, m~ny of the pr~nciples
involved can ~e appreciated from survival curves and
a basic understanding of the effect of rad~ation on
cell~ and the cellular response to damaqe.
Radlation therapy in~olves particle and
electromagnetic radiation which causes damage to both
normal and cancer tissue. Tho goal 15 to ablate the
tumor while preserving normal tissue. Th~ principles
involved are manifested in cell survlval curve~. In
Flg. 8 shown are survival curve~ with diferent
slope, a. In Fiq. 9, 7 Do . Limitlng Dose; recovery
time of normal tissue ~ 7~ . The log constant
fraction kllled for 1 . 2.3; for 2 a 1~3~
and log constant fraction recover or al and 2 -
.9 where ~~ . 3 doubling tlmes. Cells
' " .
,~
,~ .
5~3~
-- 13g --
esposed to radiation reach a treatment threshold and
then are killed e~ponentially, the survival number
~ersus radiation dose is an e~ponential curve where a
constant fraction of the cells are killed per
treatment. All tumors can be controlled as the dose
goes to infinity; however, it is the limitation of
tolerance of normal tissue not the ability to control
the tumor which is the guide to treatment. Thus, it
can be appreciated that a significant factor involved
in a cure is the first order rate constant, a, and
the initial burden No which appear in the first
order rate eguation below:
~ e-G~S~ (6)
Critical is a reduction of the tumor burden, N, to a
level which is no longer overwhelmin~ to the body's
natural defenses.
Treatment with radiation can lead to a cure even
though th$s is a local modality which has no effect
on distant micrometastase~ despite the shedding of
malignant cells by tumors which are below the mass
; sufficient for d~agnosis. Current data supports
three e~planations for this inconsistency.
(1) Only a fraction of the clonogenic cells in the
primary retain their capacity to create
metastase~ and nonclonoqenic cell8 may not
continue to grow and invade at a distant s$te.
~2) There is evidence that the host has the ability
to kill a limited number of viable metastatic
cells.
(3) The tumor mass influences it~ own metastatic
potential. Radiation therapy by diminishing the
mzss reduces the source of clonogenic metastases
and increases the host~s ability to deal with
:.
5f)~
- 140 -
residual micrometastases by eliminating the
tumor~s ad~erse effect on the host immune system.
The ideal in radiation therapy of malignant
disease is achieYed when the tumor is completely
eradicated and the surrounding normal tissue of the
treatment volume is structurally and functionally
intact. The important factor in the successful
treatment is the difference in the radiosensitivity
of neoplastic and normal cells which is the slope,
10 a, of equation 6. The difference depends on the
differential susceptibility to DNA damage,
d~fferential repair capabilities, and differential
tolerance to unrepaired damaqe as well as the ability
of normal orqans to continue to function well if they
are only segmentally damaged. ~n general, if
surrounding tissue can tolerate twice the radlation
dose of a g~ven tumor, then the tumor i8
radiosensitive. Alternately, a tumor which
estensively involves both lungs, and may be cured
with a aose of 3000 rads, cannot be trea~ed
ef~ectively with radiation therapy because of the
grsater radiosen~itivity of the surround~nq lung
tissue.
All tumors can be eradicated by treatment with
sufficient rad~ation. But, damage to normal tissue
i8 dose limiting due to the acute and late effects of
radiation therapy. Acute effectJ lncluds
e~ophagitis, pneumonitls, and diarrhea. ~hey occur
shortly after treatment and limit the size of any
given do~e. Acute effect~ are u~ually reversible and
independent of the treatment history. However,
tlssue ha~ memory in that there is a threJhold to the
total do~e accumulated over the patient's h~story
above which unacceptable late e~fects occur. Late
,':
. . . .
:.
effects are total dose limiting in radiation. They
often progress with time and are usually
irreversible. These include fibrosis, necrosis,
f~stula formation, non-healing ulcerations, and
damage to specific organs such a~ spinal cord
transection or blindness. Normal tissues and organs
differ in xadiosensitivity. The risk of
complications inGreaseS with dose, and if dalivered
by megavolt sources, in the usual fractions, occurs
when doses e~ceed the followiny: both lungs
1500 rads; both kidneys 2400 rads; liver 1500 rads;
haart 3500 rads: spinal cord 4000 rads: intestine
5500 rads; brain 6000 rads; bone 7~00 rads. While
the mechanisms of to~icity are not clear, they do not
appear to depend primarily on the rapid proliferation
of cell renewal t$ssue. Clinically they appear to
depend much more on the total dose and the size oÇ
the dos~ fraction. Acuto react~ons may be misleading
as a guide to long term effects. ~her~ are a number
of esamplQs in radiation therapy where the total dose
has beo~ incrQased, the s~ze of the dose fraction
increased or kopt the same while the interfraction
period protracted to reduce acute effects. Such
maneuvers have resulted in unacceptable late
complication~.
~here are two hypotheses for the mechanism of
lnte radiation effects. One theory attribute~ late
e~fects to th~ de~truction of connectlve tissue
stroma. The pathogene~is of llver clrrhosis i~
evidqnce that f~brosi~ can lead to organ de~truction
dospite the renewal potential of tho cells of the
organ. A variation on ~h~s hypothesis i~ that the
vasculo-connective is~ue is de~troyed due to
endothelial cell in~ury which ultlmately produces the
late effects. An alternate hypothesis sugqests that
.
.
... .. .
3~3
4~ _
both the acute and late effects of radiation are due
to depletion of the stem cell pool. Acute effects
dapend on the balance between cell killing and
compensatory replication o both the stem and
proliferative compartments. TAs development of late
efects requires that the stem cells have only a
limited proliferative capacity. Compen~ation for
estensive or repeated cell death may eshaust this
capacity re3ulting in eventual organ failure. Thls
phenoma~on can be demon~trated for mouse
hematopoietic lines. 8te~ cells can be passed a
~nite number of time~ into irradlated mice until
they lose the ab$1ity to reconstitute the recipient~s
marrow.
Successful radiation therapy can be understood
- fro~ the dynamics of csllular responses to
radiation. From the dynamic point of view, the basic
dlfference between a normal renewal tissue of the
body and a tu r i~ that in normal ti58ue there i~ an
efect~ve balance between cell production and cell
10~8; wher2a~, in tumor~, cell prolif~ration e~ceed~
cell 10~8. The normal ron2wal tlssue c~n be
con~idered a hierarchy of three type~ of cell~: Stem
cell~ - Maturing cells ~ Functioning c811s.
The cell cycle o~ cancer coll~ are in general
~horter than those of normal tl~ue. It is found in
g~eral that irradiation cJu~eJ an elongation o~ the
goneratlon cycle of tumor coll~ whlle a corresponding
~hortening of the cell cycle of normal cells i8 the
norm a~ the st~m cells rocon~tltute ~he tissue.
Dlviding cells are more su~ceptlble a~ they posses~
more D~A and repair 1~ more dl~cult.
Radio3ensitivity of normal tl~ue may be partially
esplained based on the magnitude o th~ regenerative
ro~pona-, pot-nt1ally 1ethal repair may not occur in
. ........... .
~. ~
S~3~
- 143 -
rapidly dividing cells as occurs in regeneratinq
tissue. Also, esperimen~al data indicate that
potentially lethal damage is repaired, and the
fraction of cells surviYing a given dose of X-ray is
enhanced if post radiation conditions are suboptimal
for growth. Both of these mechanisms favor tumor
cells over normal eells.
Thus, a major factor leading to a cure and which
unaerlies relative radiosensitivity iY DNA repair
capabilities. This phenomenon of repair which is
e~idenced in the magnitude of the survival curve
shoulder accounts largely for the sparing effect on
normal tissue of the multi-fraction dose reqimens
that are so commonly employed in clinical
radioth~rapy.
As with normal tissue, dlfferent tumors have a
range of radiosen~itivity some being respon~ive to a
fe~ hundred rads, and others i~curable with as much
a~ 10,000 rads, and thls variatlon can even e~ist
witbin a ~pecific tum~r type. Furthermore,
radloresistance i~ selected for in the tumor
population a~ normal t$ssue regenerative capability
declines. Thus, it can be appreciated, from survival
curves, as e~emplified in Flgs. 8 and 9, that
necessary but not suf f icient conditlons for a cure
via radiation therapy are that tha first order
klnetic~ of cell ~111 must bo such that enough cancer
c0118 are killed and the tumor doe~ not roturn to its
orlglnal ma~s in the tlme intsrval nocessary for
normal tissue to regenerate. And, th~ tumor volume
i~ reduced to a level which can be ellminated by ths
host'~ defense3 before an accumulated doss is reached
which will ultlmately produce unacceptable late
effects.
. . .
~:OC3503~
- 144 -
PH~IC~ QF ~ApIa~loN THERapY
Ionizing radiation eserts its effects on atoms
primarily as a function of the number of electrons.
Biological molecules are predominantly composed of
atoms of less than atomic wt, 15, and there is not a
lar~e difference in the magnitude of ionizations of
one element versus a~other. At a given dose,
ionizing radiation reacts with a fraction of any
gi~en molecule in its path. Therefore, a fraction of
proteins, and a fraction of DNA, etc, i damaged.
Therefore, even though it may be argued that the
number of ionizations in a cell may outnumber that o~
a critical species present at low concentrations,
only a ~raction of that species is damaged and the
c~ll can survive if it can continue to produce
proteins, replicate, and divide with estrem~
fidelity. Thu~, it is evident from a theoretical
point o view, and it i~ confirmed e~perimentally
that the critical element for survival for a cell is
to protect or reconstitute its genetic m~ssage. DNA
ha~ the ability to rapidly repair most damage but
lac~s the ability to repair double strand break~
which is the lethal e~ent in radiation therapy.
The radiation effects on particular molecule~
such a~ D~A, are ascribed to two processes, direct
and indirect action. ~y direct action i~ m~ant the
~ffect~ of enerqy directly in tho target molecule.
8y indirect action i8 meant effect~ of reactive
~peciea formed in the surroundings that dlffuse to
the target and react with it.
; - For DNA in dilute aqueous solution, the indirect
effect~ of irradiation are caused by the products
formed by the action of ionizing radiations on water
which are the O~ radical, the hydrated electron, e
aq, the H atom, H2O2, and i32.
'
~ ~ .
:
' '
:¢ .
:, ;~ t~
: ' !; 145
..~
effective species in osygenated solution is the OH
radical. This reacts chiefly with organic molecules
either b~ adding to a double bond, or by e~tractinq
an H atom from a C H bond to form H2O and a
carbon radical. The OH radical reacts essentially at
a diffusion controlled rate with DNA and DNA
components.
E~timates o~ the e~tent oS reaction indicates
that o~ the 2.7 OH radicals produced pO2 100 ev of
energy absorbed, at least .6 (20%) r~act with sugars
to produce sinqle strand breaks and le8S than 2.1
~80~) with base~ to produce modified bases. Cells
irradiated in the presence of radical scavengers have
fe~er single strand breaks. There are many
meaæurements of single strand breaks in D~A from
irrad~ated mammalian cells. Most fall in the range
of 1 to 10s~0 12 strand breaks in alkali per rad
per dalton. ~he direct and indirect ef~ects boing
about egual. And, an ef~ective diffusio~ radiu~ for
the O~ radical h~s been calculated to be
approsimately 2.3 nm.
D~A doubla strand breaks coul~ be produced by
coincidence between two independent events, by
attack on two suqars by two radicals formed in a
single clu~ter by perhaps a high ~ET particle or as a
consequon~e of ionization o~ an inner shell electron
in the D~A molecule where it i~ eDtimated that
p~rhaps 5~ of the ionization~ in irradlated DNA may
b~ a~ociatsd with innor ~hell escitations.
Esperimo~tally about one double strand bre~k, a
lethal ev~nt, i~ observed per 20-40 single strand
breaks.
. .
2~C~50~
: - 146 -
,,~
The m~chanism and bioloqical ef~ect of direct
damage to 3MA by particle or electromagnetic
radiation can be assessed by labeling the constituent
¦ 5 nucleotides with beta emitters and alpha emitters,
respectively. The ef~ects that arise from the decay
i of beta emitters incorporated into the genetic
material are single and double strand breaks, base
alterations, and inter-strand cro~s linking. Single
strand breaks can be efficiently repaired by living
cells, whereas double strand breaks are relatively
- inefficiYntly repaired and are pote~tially lathal.
In labeling e~periments, the predominant mechanism
responsible for lethality appears to be double strand
breaks caused by internal radiolysis by primary or
3econdary generated particles. For tritium labeled
D~A the probability of producing a double strand
break per decay i~ le88 than one, and the plot of
cell survival versus decay demonstrates a shoulder.
Contrarily, l2~I producQs between 2 and 12 double
strand breaks per decay e~ent by a mochanism called
an Auger ca~cade, descr$bed below. Th~ 5 involves
ejection of valenc2 electrona by an emitted gamma
ray. The plot of cell survival V8. number of decays
demonstrates no shoulder indicative of a one hit one
target mechanism. Labeling e~periment~ which label
molecule~ other than nucleotide~ demonstrate that
lothality can be e~plained br tho prosimity of the
primary or secondary particle radiation to the cell
nucleua whlch i8 consi3tent w~th the lethal event
; ~ boing nuclear damage. Lethality al~o involve~
probab~lity aa demonstrated by the inverse
relationship between the number of docay event~
needed to klll a given cell type bya radioi~otops and
tho number of radiated electrons whlch it produceJ.
. .
. . .
3~3
- 147 -
For esample Bradley et al has demonstrated that
~I is si~teen times as lethal as tritium and
Charleton and Booz calculated the electron spectrum
following decay of l25I to determine in the mean
21 electrons of high linear energy transfer are
emitted per decay via Auger cascade o electrons.
An Auger cascade is produced a~ part of a
radioactive decay path~ay inYolving internal
conver3ion. Internal conversion results in ejection
of inn~r shell electron~ called conversion
electrons. Outer shell electron~ can fill the
vacancie~ and release energy. The difference between
t~e ionization energy of the inner shell electron and
that o~ the outer shell can be released by
transmission to another olectron which is then
ejec~ed a~ an Auger electron to produce a naw
vacancy The process continue~ shell by shell until
tha valance shell is r~ached and thus leads to
multiple ionizatlon~ of the atom. Such a valency
cascade Eor elemRnts of low or med~um atomic number
the Auger electrons have energie~ up to a few KeV
with a relatively high linear enorgy tran~f~r of 1 to
; 10 ev~nm. S~nce such electron~ dissipate thair
enerqy in material~ o~ unit density within a distance
of the order of 10 to 100 nm they may eficiently
damage molecule~ in tho nQarnes~ o tho docay event.
Wlth ro~ard to radiolabelin~ D~A ono decay
eYe~t o~ a radioactive atom such a- l2~I of
internal co~ver~ion followed by an Augor ca~cade
which cause radioly~i~ and double strand broakage i3
- lothal to a coll. Radiation th~rapy i~ ar le~s
e~ficient requlring approsi~ately 105 photons
; ab~orption events per CQll to produce the same lethal
event. MI~AGE therapy accomplishQs the same end
point as the~e modalities without the use o~
, ~
~Ot~
- 148 -
radioactive atoms and with electromagnetic radiation
do~es one m~llion times less tha~ that of
conventional radiation therapy. This is accomplished
by utilizing phenom~non common to electromagnetic
radiation therapy and radioactive atomic D~A
labeling. ~IRAGE therapy entails usinq Mossbauer
atomi~ labaled pharmaceuticals which bind to the
genetie ~ateria~ o~ the target cell and resonantly
absorb gamma radiation to eY~ite nuclear
transitions. Nuslear escitation produces a
radioacti~e atom from a stable ato~, and the
con~equences are the same as for the case o~ l2gI
labeled DNA. Furthermore, thi~ single event will
kill the target cell which is in contra~t to
conventional rad~ation therapy where multiple
improbable e~ents mu~t occur simultaneou~ly to
produce a double strand break. 105 photons by
conventional therapy versus one for M~AGE therapy
are nscessary to eradicate the target cell. Also,
much lea~ photon flus i~ needed for MrRA OE therapy.
The absorption cross-section for wster the primary
target of conventional radiation therapy i~
approsimately 10 25 cm2, wherean the resonant
cro~s-section for Mossbauer absorption i~ 10-17
cm2 which repreaents an eight or~er o~ maqnitude
imyrovemant. Thls increased efficiencr permit~ cell
k~ll with radlation doses of ono milllonth that of
con~entional thorapy.
P~S~ A~ C~L~ F MIR~E-~5~3aEy
; W1~_12~22fW A~ A~ ExA~ELE~
The primary decay of the ma~oritr of radioactive
nuclides produce~ a daughter nucleu~ whlch i~ in a
highly escited state. The latter thon de-escitEs by
emitting a s~ries of gamma ray photon~ until it
(33~
- 149 -
reaches a stable ground state. The Mossbauer effect
occurs when the gamma ray emitted during a transition
to a nuclear state is used to e~cite a second stable
nucleus of the same isotope; thus, giving rise to
resonant nuclear absorption. This i5 an extremely
monochromatic event. The degree of monochromaticity
can easily be shown from the Heisenberg uncertainty
principle. Tha ground state of the nucleus has an
infinite lifetime, and, therefore, there is no
uncertainty in its energy. The uncertainty in the
lif time of the e~cited state is given by its mean
life, ~ , and the uncertainty in its energy is given
by the width of the statistical energy distribution
at half height,r . They are related by
j~ r~,~ t7)
~ is related to the more familiar half-life of the
state by ~ ~ ln2~tl~2. If r i~ gi~an in electron
volts and tl~2 i~ in seconds, then
r = ~ 5G~X /,~t, (8)
For a typical nuclear e~cited-state half-life of
r~ tl~2 ~ 10 7seconds, r 4.562~10 9eV. I the
energy of the e~cited state is 45.62 XeY, the emitted
g~mma ray will have an intrinsic resolution of one
part in 1013, For comparison, the ma~imum
reaolution obtained in atomic line spectra is only
about one in 108. In fact, the line width i~ so
narrow that its energy can be Doppler shited by
driving the source at moderate velocities or side
bands in the emission energy can be created by
driving a stationary source at ultrasonic frequencies
where the energy of the side bands is continuously
~5~3~3
- 150 -
tunable by varying the ultrasonic driving frequency.
It is the capability of shifting the energy of the
source to cause resonant absorption in an absorber
ato~ incorporated as part of a pharmaceutical
molecule that permits the use of this phenomenon to
selectively treat disease such as cancer.
The Mossbauer effect is degraded by recoil
energy of the emitted and absorbed photon. This
limitation can be circumvented by binding the
Mossbauer source and absorber atoms into a massive
lattice or molecular structure. The recoil energy is
given as follows: E ~
r = ~r
~R ;~ ~ ca (g)
This equation indicate~ that as the mass of the
structure into which the ~ossbauer atom is
incorporated goes to infinity the recoil energy goes
to zero. To accomplish this the source atoms are
incorporated into a lattice or metal and the absorber
i~ incorporated into a pharmaceutical which binds to
a m~ssive molecule or i~ incorporated into a
biological lattice. Esample~ include DNA and bone
m~tri~, respecti~ely. For the former case, the
Mossbauer atom i~ bound to a pharmaceutical by
co~alent, chelation, or coordinate bonds and the
pharmaceutical molecule binds to DNA by hydrogen or
co~alent bonding, electrostatic interaction~, or
intorcalation.
Structure~ which bind to DNA to form e~tremely
stable comple~es with duples D~A by hydrogen bonding
and electrostatic interactions and wh~ch could be
w ed a~ part of a MI~GE drug include netropsin,
distamycin A, and anthramycin. And intercalating
structures which could be used to produce a MIRAGE
03~3
- 151 -
drug include ellipticinium, quinacrine, actinomycin,
mithramycin, ethinium, adriamycin, acridine orange,
nogalamycin, propidium, anthracyclines, psoralen,
duanarubicin, bithiazole, olivomycin, chromomycin
A3, acridine, chloroquine, quinine,
8 amino-quinolines, quinacrine, proflavin~
bleomycins, phleomycins, mefloyuine, mito~antrone,
and others which represent modification of the
mentioned basic molecular structures.
See Table 6 for the structure of DNA binding
molecules and see Figs. lOA, ~ and C for a diagrams
of MlRAGE drug 12~29/W and it~ mechanism o
intercalation. In the proposed mschanism the
bithiazole rings bleomycin, a~ shown in Fig. lO~,
intercalate between base pairs in which one chain
contains a G-T or G-C sequence.
Degradation of the Mo~sbauer effect via recoil
o~ the en~ire atom can be prevented by bonding it to
r a massive ob~ect; however, nuclear r0coil energies
are of the order o magnitude of lattice-vibration
phonon energies and the Mossbauer effect can be
degraded if the recoil energy eYcites one of the
quantized vibrational level~. The probability that
one emis~ion or absorption e~ent will occur without
vibrational deqradation i~ given by the parameter f
which i~ known a~ the recoilles~ or recoil-free
~raction. To increa~e the relative strenqth of the
r~coille~s re~onant proce~s, it i~ im~ortant that f
be a~ large a~ possible. The recoille~s f ractlon f
can be related to the vibrational properties of the
crystal lattice by
X ~ ) (10)
(~ C~
r~ t
-- 152 -
where ~ x2 ~ is the mean-square vibrational amplitude
of the nucleus in the direction of the gamma ray.
From the form of the esponential, f will only be
large for a tightly bound atom with a small
mean-square displacement and for a small value of the
gamma ray energy, ~. F can b~ increased for the
source by cryostatically cooling it, and f can be
increased for the absorber atom which is part of a
-: pharmaceutical by increasing the bond strength of the
. 10 atom with the remaind~r of the pharmaceutical
- molecule.
As described previously, Auger cascades in DNA
binding pharmaceuticals cause DNA radiolysis and
concomitant death of the cells in the target tissue.
. 15 The equation which relate~ the number of internal
c conversion events with concomitant Auger cascade to
nuclear parameters is given as follows:
; ` B = ~Ofn,0' (1l)
where B i~ tha number of internal conver~ion events,
~ i8 the Auger cross-section, f i~ the recoilless
fraction, n is th~ number of Mossbauer atoms, and
is the photon flu~. ~O i~ entirely determined by
nuclear paramaters and i3 given by the following
eguation:
( E~, J ~; r / / o~ ~12)
~t3~3~
- 153 -
(~-Ey) ~(r~l) ( 13)
:` ,
.~
where equation 12 gives the masirmum cross-section,
, at E~Eo, and equation 13 is the cross-section
for resonant absorption. Ie and Ig are the nuclear
spin quantum numbers of the escited and ground
states, r i5 the line width, and c~ is the internal
conversion coefficient which is the ratio of the
number of conversion electrons to the number of gamma
ray photons emitted. To generate an effective MIRAGE
drug, a Mossbauer atom with a large Auger
; 10cross-section which emits multiple Auger electrons of
high linear energy transfer of the range 1-10 ev~nm
i~ used. Esamples o isotopes with large Auger
cross-sections are given in Table 8 where the valus
for ~7Fe is given as 2.2~10 17 cm2.
15The number of targets, n, i8 depandent on the
binding constant of the drug with DNA. The
bithiazale qroup of Bleomycin ha~ a ~ of the 106
which re~ults in one Bleomycin molecule bound per
eight nucleotide~. This represents at least 109
t~rqet atom~ per cell. ~ntercalating drugs such as
biacrid$nes have ~d's o~ th* order of 1011; thus n
c~n be made even larger. And, drugs which use
~ifferent mode~ o~ binding can be use~ in
comb$natlon. For esample, the D~A molecule can
~1 become saturated with intercalated drugs but retain
the ab$1ity to bind a drug which binds by a mode
different than intercalation. An e~ample is
Netropsin which binds esternally to the DNA molecule
by electrostatic interactions. N can be increased by
~0~ 3~
~ 154 -
u$i~g a combination of dru~s such a~ acridlne and
N~troesin analoyues where binding is by intercalation
and electrostatic interactions, respectively.
.
3~ 3~3
.~ - 155 _
Y ~ U e ~ o ~ r y ~ ' ~ o o o~ ~ _
~ .
~r ~ O~ O
y ~ I ~V O O ,, ,0~ 0,.OO ~O , ~O~O ~ ~.
=~5 ~Z v~ O~q ~ og2~
! 1 3 ~ - - ~` ~ æ o l~ _O ~ 0 0~ O
~ ;~oui ~ ~ t oOo,
-- lS6 ~
MIRAGE drugs must be desi~ned such that they
have a high recoilless fraction which is a function
o~ the vibrational energy of the bond linking the
Mossbauer atom to the pharmaceutical. The energy of
molecular vibrations ha~ a range of 5-50 KJ; whereas
lattice vibrational energies range between 0.5 to
5 KJ. As a comparison, the vibrational energy of Fe
- metal at room temperature is 1 KJ. To achirve a high
recoilless f:action the vibrational energy should be
an order of magnitude greater than the recoil energy
which i~ 0.1 KJ for 57Fe For e~ample, the
vibrational energy of Fe metal is an order of
magnitude greater than the recoil energy, and f for
57Fe metal at room temperature is o. 7. F should
be higher for 57Fe~Bleomycin because ~ for tha
coordination o iron wit~ 31eomycin i~ 109 which
gives a ~G of appro~ima~ely -50 KJ and a vibrational
energy oS approsimately 5 XJ by thermodynamic
calculations.
Since covalent bonding yield~ h~gher vibrational
energies, the Moss~auer atom should be covalently
bound to the i~tercalating function. Many of the
Moss~auer isotopes form covalent bonds with organic
molecule~. Esample~ include Mossbauer isotopes of
tin, a~timony, tellurium, iodino, germanium, and
mrrcury. Lanthanide ~o~sbauer i~otope~ such aJ
gadolinium, dysprosium, ~amarium, and europium form
cholation compound~ with ~ of the order of
10 . Mo~sbauer i~otopes can alJo be involved in
organometallic bounding such aJ occurs between iron
and cyclopentadiene and between o~mium and
cyclopentadiene in ferrocene and o~mocene,
re~pectively. Vibrational energies for these
compounds i~ appro~imately on~ tenth the bonding
energie~ which are of the order of 300 RJtmole.
75~3
- 157 --
Thus, ~he recoilless fraction for pharmaceuticals
in~olvin~ thi~ bonding would be high. Esamples of
MIRAGE pharmaceuticals are given in the Esempla~y
Material Section.
Usinq ths pre~iously described nuclear a~d
thermodynamic parameters, a calculation of the dose
necessary to achieve therapeutic e~icac~ can be
calculated for l2~29/w and compared to th~ actual
e~perimental effect which appears in the Esperimental
Section. For sJFe the Auger cross-section is
2.2Slo~l7 c~2 where G~ ~ l0 and internal
conversion occurs greater than 90% of the time.
Greater than l0 conversion electrons and Auger
electrons are emitted on averaqe per transition as
appeared in Fig. ll. The binding constant o
Bleomycin ~o DNA is lo6 which corresponds to the
number of targets, n, ayual to l09. The ree
energy of binding of iron to Bleomycin i3 50 KJ which
predicts a recoilles~ fract~on, f, of approYimately
one. One nuclear escitation ev0nt followed by
internal conYersion produces a lethal hit. The
necessary photon flus to effect this e~ent is
calculated using equation ll a~ follows:
~ 107 ~hat~n~
: ~109) ~1) (2.2~Lo-17) C3
;,
The dose due to this photon flu~ is calculated
as follows for the 14.4 geV qamma ray of a ~Co
source using the equation from Table ll,
206~ 3~39
. . .
-- 158 --
o
E~ ~n ~0 U ro
~ 1~ o. e ~ ~ ~
0 ~
-~ -~ ~ a O
h ~ u
aJ X ~ X
_~ O ~ O
a o 0 x u~ ~$ s u
E~ ~ ~ o ~On ~ C
x x e~ x vJ ~s ~3 0 c
1~ c E~ U~
E-' U ~ o ~ hW O ~
x _~, c u O u ~ ~e
t~SU'UC-C uc'c ~C
¢ x
c
¢ ~ cu~ a
~î
~ n ~
u ~ ~n
;;~0~ 3~
- 159 -
.
whsre 70% of the energy is absorbed in lcm:
Dose =
(.7) ~.S~LO7phoeons) ~1~.4:~L03ev~ ~1.6slû-LgJ) (107~q)
~ ' _
c~o ) ( ph~on ) ( Q~
X l~ad
7 ~ ~ad
lOO~rq
This can be compared with the m rad levels of
Mossbauer radiation which were found to be effective
in the esperiments indicated in the Esperimental
Section.
Esploitatlon of the Mossbauer effect permits
drugs which will eradicate target cells using levels
of radiation which are comparable to background
- level~ and woll b~low levels that are necess~ry to
cause acute or late e~fects of radiation therapy.
Furthermore, MIRAGE therapy is a modality whereby the
side effect~ of chemotherapy cDn be eliminated.
MIRA OE drugs dre desiqned such that they bind to
t~rget~ such a~ DNA and the therapy i~ conducted in
such a mann~r th~t the Mos~bauer effect will be
caused to occur in the space occupied by the target
_ cell~, but nut to a siynificant e~tent in the
nontarget cell locationg by mochanisms to be
described below. The binding can be nonto~ic.
Representativo nontosic structureg are p~oralens used
for the treatment or psoriagis, quinacrine and
acrldine drugs used for parasitic diseases, quinoline
~O~D~3~:~
-- 160 --
drugs used for the treatment o~ malaria,
thio3~n~henone drl~gs used for the treatment of
Schistosomiasis, and Tilorone, an antiviral drug,
(see Table 6 for structures).
The parameters involYed in fabricating a
pharmaceutical using other Mossbauer isotopes are the
same as those discussed for ~Fe. For esample
~, and ~2,T~ can be covalently
linked to intercalating molecule~. The bond energies
are typically 400-500 RJ~mole which implies
vibrational energiec of 40-50 XJ~mole. This is well
above an order of magnitude the recoil energies which
are .25 XJ~mole, .59 JR~mole, and .52 RJ~mole,
respectively. Thus, a recoilless fraction, f, of
appro~imately one i~ predicted. The Au~er
cross-sections from Table 8 are 7.16 ~ 10 18 cm2,
2-17 ~ 10 18cm2 and 3.61 s 10 18cm2,
re~pectively. l~S~ ~lsb~ and l2~Te are
approYimately the same atomic number as l2~I where
the latter radioact$ve isotope e~ect~ 21 electrons
during an Auser cascadQ inYolving the K shell. These
former Mossbauer isotopes are predicted to e~ec~ the
same number of electrons becau~e internal conversion
i~volveJ K and L shell~ as demonstrated in Figs. 12,
1~, and 14. Synthatic pathways for e~emplary MIRAGE
drug~ incorporating the ~ossbauer i~oto~es l~9Sn,
~lsb~ and l~9Te and other isotopes from
Table 7 appear in the Esemplary Materlal Section.
Selective killing of selected c~lls with sparing
of nonselected colls can be achieved by several
mechanisms:
:,
' '
3~3
- 161 -
1. The use of pharmaceuticals where their chemical
and physical properties e~ploit bioloqical
phenomena.
2. The use o~ pharmaceuticals which have a
different isomer shift, quadrapole hyperfine
splitting, or magnetic hyperfine splitting in
selected ~ells ~ersus nonselected cells.
3. Applying magnetic or electric fields in the
space occupied by the selected tissue so that a
hyperfine line is c~eated for the salected
tissue which i~ absent for the nonselected
tissue.
4. Polarization of the incident gamma rays with
re~onant polarization o~ the absorbers in the
selected tissue and not in the nonselected
tissue.
S. Applying a collinated or focu~ed ultrasonic beam
along a line p~th that intersects the
administered gamma ray~ at the ~lected tissue
~lte where the former beam escite~ a component
o~ ultra~onic motion o~ the Mossbauer absorber
- nuclei in th~ direction of the latter beam to
produce absorption side bands and where the
gamma rays of the second beam are of energy
re~onant with the side bands.
For ca~e 1
MIRAGE therapy can achleve selectivity in the
c~8e 0~ cancsr th~rapy in animal~ includlng human~
vi~ e~ploiting known selsctive uptake by canc~r cells
of compounds such a~ Bleomycin, cationic lipophilic
d~es ~uch a~ Rhodanine, hematoporphryins, and
monoclonal antibodies. In these case~, a Mossbauer
isotope or MIRAGE pharmaceutical i~ bound to the
compound known to be selectively taken up by the
~o~
- 162 -
cancer. In contrast to chemotherapy, the selectivity
need only be relative to other cell types in the
~ossbauer radiation field.
The MIRAGE pharmaceutical in~lude~ thos~ formed
by derivatizinq a D~A binding molecule of Table 6
with a MossbauRr absorber atom o Table 7 as
described in the General Synthetic Pathways and
Esemplary Materials Sections. The carrier a~d MIRAGE
- pharmaceutical are attached by a co~alent bond such
a~ a disulfide, a~ide, e~ter, ether, amine, or
car~on-carbon bond which iB formed by using e~istinq
functional groups or ~y placing functional groups on
the carrier and MIRAGE pharmaceut$cal such as
carbo~yl, amino, sulfide, halogen, or carbonyl and
conden~ing the two entitles toqether by methods
generally known to one skilled in the art.
Colloids such a~ those of gallium are known to
be concentrated by certain typ~s of cancer cells and
the same phenomenon i~ predicted for certain colloids
of Mossbauer i80tope8 compriBing massive inert
carriers ~uch a~ those described in the
Macromolecular M~RAGE Pharmaceutical Section.
Carriers of 108 daltons or groater ars espected to
be efective in permitt~ng the Mo~sbauer effect to
occur. Also, many Mossbauer i~otopes includ~ng
m~tallic and inorganic forms are capable o~ bein~
i~corporated into blological matrice~ including bone
which i~ useful for tho treatment o~ metastatic bone
cancer. E~amples include ~R, ~Gd,
l~lDy l~y l~m l~u, l~Gd~
and ~o~ compounds described proviously in the
Macromolecular MIRAGE Ph~rmaceutical Section.- And,
aJ further d~3cr~bed in the ment~oned section,
Messbauer isotopes can be incorporated into other
~()&35()~3
- 163 -
biological molecules. For esample, Mossbauer
isotopes l2,I and l~I can be incorporated
into thyroid hormones and the precursor molecules of
thyroid hormones. ~11 can serve as targets for
treatment of thyroid cancer with MIRAGE therapy. And
Fe can be incorporated into h~me proteins and
red blood cells. The latter tar~et can he irradiated
at the frequency of deosyhemoglobin which d~ffers
from that of osyhemoglobin to esploit the relative
hyposia of tumors where hypoYia re~ults in a greater
concentration of deosyhe~oglobin. Furthermore,
damage to the red blood cell~ in the tumor leads to
coagulation ~ollowed by thrombosis of the blood
supply to the tumor and concomitant tumor death.
For case 2
The energie~ of the nuclear states are weakly
influenced by the che~ical environment. The energies
of these perturbat~ons relati~e to the energy of the
nuclear tran~ition~ in the absence of eects from
the en~ironment are of the order of 10 10.
However, the line width of the Mo~sbauer effect is
estremely narrow with monochromaticity of the order
of ono part in 1013. Thi~ pormits selective
ab~orpt~on in a spatial region containing selected
colls where these estremely small effects differ from
tho~e of the background value of nonselected ti~ue.
,d Th~re are three principle interactions, the
chemical isomer shift, tho magnetic hyperfine
interaction, and the ~uadrapole hyperfine interaction.
~
Th~ nucleus which i~ charged interacts with the
oppo~itely charged S electron den~ity which
penetrates to the nucleus. For esample, the
2(~5(t3~
- 164 -
integrated coulombic energy ~or an electron of
charge - e moving in the ~ield of a point nucleus of
charge +Ze is given by:
Eo ~ ~J~ r (14)
where Eo is the permittivity of a vacuum, r is the
radial distance, and- ~ ~ is the charge density of
the electron in volume element d~. When the nucleus
underyoes a transition, the size of the nucleus
changes which results in a change in the electric
monopole or coulombic interaction between the
electronic and nuclear charges.
The energy of radiation which produces resonant
absorption is a function of the effective electron
density at the absorbing nucleus: thus, it shifts as
a consequence of a change in the nuclear S electron
density. ~his is seen a~ a shift of the absorption
line away from zero velocity and is variously known
as the chemical isomer shift, or centrs shift, and is
ds~ignated by the symbol~ . The Mossbauer ezperiment
compares the difference in enerqy between the nuclear
transitions in the source and absorber, so that the
chemical isomer shift as observed is given by
S=S~, ze R SR fiJ(~s( )50~b~ 5~urcei~
where R is the nuclear radius, e is the charge of an
electron, and Z is the atomic number and¦ ~S(0) ¦is
the non-relativistic Schrodinger wavo f~nction at
q ~ 3 ~
- 16~ -
r = 0. ~his can be related to the measured Doppler
velocity units, v, by
~ (16)
In equation 15, ¦ ~S(O~¦is the s electron density
at the nucleus, and not the s electron o~cupation in
the formal chemical sense. If ~ R/R is positive,
a positive value of the chemical isomer shift,~ ,
implies the s electron density at the nucleus in the
absorber is greater than that in the source ¦ ~s(~)¦
includes contributions from all the occupied
s electron orbitals in the atom, but is naturally
more sensitive to changes which take place in the
outer valance shells. Althouqh the values of
¦ ~5(O) ¦ for p, d, and f electrons are zero, these
orbitals neverthele~s do have a significant indirect
interaction with the nucleus via interpenetration
shielding of th~ s electrons. For e~ample, a
; 3d54sl configuration will have a larger value of
¦ ~5(o)¦ than 3d64sl because in the latter case
- the estra d electron shields the 48 electron from the
nucleus.
M~E3IS~HYPERFIN~ LXIEEAS~IO~S
The nucleus has a magnetic moment, ~, when the
8pin quantum number, I, is greater than zero. Its
energy is then affected by the presence of a magnetic
field, and the interact$on of ~ with a magnetic flu~
_ donsity of B i8 formally e~pressed by the Hamiltonian
.. . .
~ .
3~3
- 166 -
where ~N -27 2 nuclear magneton
(eh/4 mpaS.049~10 Am or J~T~ and g is the
nuclear g-factor [g-u/(I ~h )]- Solving for this
Hamiltonian gives the energy levels of the nucleus in
th0 field to be
E" ~ Z ~ (18)
where mz is the magnetic quantum number and can
take the values I, I-l, . . . -I. In effect, the
magnetic field splits the eneryy level into 2I+l
non-deqenerate equi-spaced sublevels with a
separation of ~B~I. For a Mossbauer nucleus, there
may be a transition from a qround state with a spin
quantum number Ig and a magnetic moment ~g to an
escited state with spin Ie and magnetic moment ~e.
In a magnetic field, both states will be split
according to equations 17 and 18. In NMR, radio
frequency transitions occur within nondegenerate
levels o~ the ground state; whereas, for the
Mossbauer effect gamma ray transitions take place
between nondegenerate magnetic sublevels of the
ground and e~cited nuclear states provided that the
solection rule ~mz , o, ~ 1 is obeyed tthis is
c~lled a magnetic dipole (Ml) transition which is the
predominant transition]. As the result of the
presence of an internal magnetic field which can be
generated by an unpaired elsctron in the atomic
environment that can induce an imbalance in electron
spin density at the nucleus or by an e~ternally
applied field, the degeneracy of the ground and
e~cited nuclear level i~ lifted. The resultant
Mossbauer spectrum contains a number of resonance
. -
'''i~ , . . .
,, .
- 167 -
lines, but is nevertheless symmetrical about the
centroid. A typical e~ample of magnetic hyperfine
splitting is illustrated in Figs. 15A and s which is
drawn to a scale appropriate to 119Sn. For this
isotope Ig=l/2, Ie = 3f2, ~q = -l.041~N and
~e 0-67~N. The change in ~iyn of the
magnetic moment results in a relatiYe inversion o
the multiplets. The sis lines aro tha allowed
- ~mz = O, 1 transitions, and the resultant spectrum
is indicated in the stick diagram. The lines are not
of egual intensity, but the 3:2:1: 1:2:3 ratio shown
here is often found for esample in the 5~Fe and
ll~sn resonances in randomly oriented
polycrystalline samples. A more detailed account of
the relative intensities is given in the diseussion
of polarization o~ gamma rays.
OUAD~O~ HyPERFItlE INTE~,A~ON~à
Mo~sbauer nuclei with nuclear state3 with I 1~2
have a nuclear guadrapole moment. An electric
quadrapole interaction between the nuclear quadrapole
moment and the local electric f~e~d gradient tensor
at the nucleu~ produces a multiline spectrum as wa~
th~ case for magnetic hyperfine ~plitting. The
electric quadrapole lnteraction in ~ossbauer
~pectroscopy is very similar to that in nuclear
~uadrapole r~sonance spectroscopy. The main
d~fference is that the latter i~ concerned with radio
frequency tran~itions within a hyperfine multiplet of
a ground state nucleug, whereas, the former is a
gamma ray transition between the hyperfine multiplets
of the nucleus in its ground and e~cited states. The
electric field gradient is determined by the
electronic occupancy o~ atomic orbltals and is
1nfluenced by the oonding to other atoms. Also, in
.
"'
.:
:
;~ :
' ' -
~Q~r~ 9
- 168 -
some compounds, the MossbauPr atom has an
intrinsically high symmetry (e.g. Fe3~ dS ion has
a half filled shell and is a spherical s-state ion)
but may still show a quadrapole splitting. The
latter originates from charges esternal to the atom,
such as other ions, which polarize the spherical core
and can induce a very large electric field gradient
at the nucleus.
Selectivity in the eradication of selected cells
while sparing nonsalected c~lls can be achie~ed where
a change in the isomer shift, maqnetic hyperfine, or
quadrapole hyperfine interaction is realized in the
selected cells which i5 different from that of
nonselected C811s. For esample, cancer cells are
known to have di~ferences in ion concentrations and
ph from normal cells. Binding of an ion or molecule
such as a proton (in ths case where the MIRAGE
pharmaceutical is a weak acid or weak bse with a pKa
or pXb, respectively, which i~ a~prosimately equal to
the pH of the organic media at the selected tissue
site or the nonselected tissue along the ray path of
the administered gamma rays) could result in a change
in the electronic interaction at the Mossbauer
nucleus and result in a distinct spectrum. Also, the
pre~ence of a protein in the tarqet cell which binds
to the drug to affect the spectrum could also provide
discrimination. -This mechanism i5 discussed in more
dotail under MI~AGE A~DS Drug.
. .
For ca~e 3
Th~ nuclear spin moments of Mossbauer i~otope~
become aligned in an imposed magnetic field. The
pre~ence of the field lit~ the degeneracy oÇ the
quantum state~ and the nucleus mugt occupy one of
these quantum states. Transitions between magnetic
~ .
- 169 -
sublevels of nuclear states during resonant
absorption results in a multiline spectrum. The
energy of the tra~sitions, and thus the positions of
the lines, are directly proportional to the magnetic
field strength~ Therefore, by manipulating the
esternal magnetic field strength a transitio~ between
: magnetic sublevels of thQ ground and e~cited nuclear
states can be created in the spatial regio~ of the
: ~elected tissue such that the energy to achieve
resonance is dlstinctly different fEom that which
achieves resonance in the surroundi ng nonselected
tissue. This is achieved when the resonant energy of
the selected tissue is shifted by one line width from
that of nonselected tissue. The energies and the
d~mensions involved are calculated Eor ~l~Sn as
follows: The line width for 1~Sn is
2.57slO 8ev, the magnetic moment i~ -1.046 ~
which resonate~ at 32 MHz for a 2T field. This
represents an ener~ of 1.~2210 7 e~. ~his energy
i~ directly proportional to the maqnetic flus
density, and a realistic ~lu~ density grad~ent is
2000~uass~cm or 10% of the flus den~ity per cm.
Since the line width is 20~ of the magnetic energy, a
20% cha~qe in the flus density is nocessary to shift
the resonant energy by one llne width. This
relationship gives 2cm as the spatial displacement
for whlch the nonselected surround~ng tissue becomes
trAnsparent with rsspect to the Mosabauer effect to
tho radiation which is resonantly ab~orbed by the
30 5elected ti~sue.
. . .
For ca8e 4
. Selective absorption in a predetermined region
: of space can be accomplished by polarizing the source
ga~a rays and by aligning the spln momants of the
.~
'
~.'
:.
., .
- 170 -
selected absorber nuclei wîth an external maqnetic
field in a vector orientation relative to the
incident polarized gamma ray to permit a nuclear
transition between magnetic sublevels which is
quantum mechanically allowed only for the proper spin
moment alignment. Polarized yamma rays can be
obtained by three methods, magnetized ferromagnetic
sources, quadrapole split sources, or falter
techniques a~ shown by U. Go~ser and H. Fischer,
CU~re~ Topic~ the Phy~ic5___l~__ MQ~ u~
Resonance Gamma Ray Polarimetry, 99-135; incorporated
by reference.
Selectivity via polarization of the source and
absorber nuclei is possible due to the polarization
and anqular dependence of transitions between
hyperfine quantum sublevels. ThH intensity of the
emitted or absorbed rad~ation a~d its dependence on
orientation are determined by conservation of angular
m~mentum in the system of nucleus plus qamma ray
~quantum select$on rule~) where the
quantum-mechanical treatment of electromagnetic
rad$ation leads to the introduction of photons which
are bosons of vanishing rest mass and quantized
angular momentum. The intensity of a particular
hyperfine transition between quantized sublevels is
d~termined by the couplin~ of the two nuclear angular
momentum state~. It can be espressed a~ the product
of t~o term~ which are angular-dependent and
angular-independent, respectively.
` Tho former averages to unity for th~ case of the
em$ssion from a source or absorption by the absorber
nuclei when all orientations of the magnetic a~e~ of
the nucle$ are equally pos~$ble. Such a case e~$sts
` 35 or a randomly oriented polycrystalline powder sample
2~ g
- 171 -
where an internal field esists. The intensity in
this instance is given by the square of the
"appropriate Clebsch-Gordan coefficient:
~ Pnsl ~y o~ ~ I, J ~ > (l9)
where the two nuclear spin states Il and I2 have
5I2 values of ml and m2 and their coupling obeys
the vector sum J Il~I2 and m=ml-m2. J is
referred to as the multipolarity of the transition,
and the intensity is greater if J is small: if J=l,
it is re~erred to as a dipole transition, while with
10J=2 it is a quadrapole transition. Most of the
Mossbauer transitions take place without a change in
parity, so that the radiation is classified as a
magnetic dipole (Ml) or electric quadrapole (E2)
transition. The selection rule for an Ml or El
15transition is ~mz=0, ~ 1, and for an E2 transition
i~ ~mz 0,~ 2-
The most frequently used coefficients are those
for the 1/2-~2 Ml transition, and these are given
in Table 9. Il, may be either the ground or
20escited state spin. Although there are nominally
eight transition3, the +3~2- 1/2 and
3~2~+1~2 transitions, have a zero probability
~forbidden). The sis finite coefficients, C~,
which espress the angular-independent intensity have
;- 25a total probability of unit intensity and give
d~rectly the 3:2:1:1:2:3 intensity ratio~ for a
magnetic hyperfine splitting, shown in Fig. 16. The
corresponding terms for a quadrapole spectrum are
obtained by summation and give a 1:1 ratio.
- `
~ 17~ _
Table 9
The Relative Probabilities for a 1/2,3~2 Transition
. _ . _ . _ . . _
Magnetic spectra (Ml)
C C2 3(J,m)
m2 -ml m ~1) (2) (2)
_
+~ (1 + cos2 ~)
2 J3 6 2sin2 ~
-2 +2 -1 Jl 1~ 4~1 + cos2 ~)
-2 +2 -2 o o
: +~ -1 +2 o o
- 1 -2 +1 ~ 12 ~(1 + cos2 Q)
-2 -2 ~ sin2 ~
~ -1 1 4 4(1 + cos2 ~)
Quadrupole spectra (Mlj when ~ = O
c2 9(J,m)
Transition (2) ~2)
. _ _ . _
+ ~sin2 9
~ (1 + cos2 9)
`'! ( 1) The Clebsch-Gordan
coefficient
(2l-mlml2 m2)
(2) c2 and ~J,m) are the angular-indeeendent
and angu ar-dependent terms normallzed to a
: total radiation probab~lity of
~ C29(J,m)al
~: mlm2
~'
~Q ~
- 173 -
The anqular dependent terms, ~(J,M), are
espressed as the radiation probability in a direction
at an angle a to the quantization a~is (i.e. the
magnetic field axis or the principle electric field
a~is- note that the values in the la~ter case are
only correct if the electric field gradient about the
principle asis is symmetric~. The intensity for a
polycrystalline sample is obtained by integration
over all ~ to obtain a (J,M) as follows:
n~=~JJ(/1S~ g)s (20)
o
and the total of emitted radiation is independent of
o and normalized to unity, i.e.
s ~I~J-m~
, - tn, ~
Coefficients such as those in Table 9 are necessary
to interpret the angular dependence of the spectrum
fro~ a single crystal or oriented absorber. For
example, a magnetically ordered metal alloy or oside
absorber may often be polarized by magnetizing in a
- small e~ternal magnetic field to give a unique
direction of the internal field. The expected line
; intensities ca~ then be predicted from Table 9 to be
`~ 20 ln the ratios 3~ 1:x:3 where
- 4 sin2o/(l~cos2o); in particular, the
~m ~ o transitions have a zero intensity when
observed along the direction of the field (a-0)
and a maximum intensity perpendicular to the field
to-90). Thls is illu~trated schematicall~ in
Flgs. 16A and 8.
,i . '
i4)~39
- 174 -
The equivalent hehavior in the quadrapole
spectrum is a 1:3 ratio for the gamma ray a~is
parallel to the direction o the principle electric
field gradient axis and 5:3 ratio p~rpendicular to
the principle asis.
The angular dependence of the polarization
absorption phenomenon is demonstrated esperimantally
as summarized in Figs. 17A, B. The spectra in
Figa. 17 were obtained with a sinqle crystal of
a-Fe20~ (hematite). Ths crystal was cut
parallel to the basal plane and measured ~a) at
80R and (b) at room temperature. Th~ change in
the relative line intensities indicates a
reorientation of the spins (Morin transition). Below
the Morin temperature (Tm 260K), the spins
'- 15 are oriented perpendicular to the basal plane o~ ths
rhombohedral ~tructure and are parallel and
antiparallel to the gamma ray direction. Thus, the
~m . o line~ disappear. Above the Morin temperature
the spin~ 1ip and align into the ba~al plane and the
; 20 ~m - O line~ become strong.
Selective eradication of a selecte~ cell line
' such a~ cancar tissue can be achieved by polarizing
th~ cancer t$ssue with an orientation different from
surrou~ding normal tis~ue, and by irradiatinq with
r~diation whlch e~cite~ the corresponding
tran~ition. For esample, referring to Fig3. 17A and
~, the nuclei o~ the MIRAGE pharmaceutlcal present in
r, th~ cancer tlJsue can be aligned porpendicularly to
the propagation direction o the gnmma ray; whereas,
`' 30 the Mo~bauer nuclei present in normal ti~ue are
aligned' parallel to the gamma ray propagation
direction where alignment in both cases is achieved
wlth an e~ternal magnet$c field. By irradiation with
ga~ma rays which are re~onant with tho ~m 3 0
transition, only the cancer tissue will ab~orb the
radiation.
5()39
- 175 -
For Case 5
The line shape ~or either an absorption or
emission Mossbauer line is given by
W ( ) = 17JQ(t) - ( 7-,. ) Itt ~`-; w t
--aO
~ where the correlation function
- ~(t)~ (t) e;~-x()I,r,> (23)
where Xo is the displacement of the nucleus from its
equilibrium position;~ k is the momentum of the gamma
ray; and the bar devotes a thermal average;~ W:~ ~ Et,
where Et is the difference in energy between the
initial and final nuclear states, r is the natural
line width of the nuclear escited state; and Im>
represents the phonon states of the absorber or
source. For the case of harmonic phonon states, the
factor ~ (t) predicts a broad ~ackground to the
Mossbauer line duc to the distribution of thermal
' 15 phonons in the source or absorber. However, if the
source or absorber is e~cited ultrasonically at a
single ~reguency ~V0 , the behavior of ~(tJ, and hence
the line shaps is altered drastically. The line
~hape of an idaal crystal of harmonic phonon states
for the two cases in which the phonon rela~ation
time; the time it takes the initially monochromatic
ultrasonic beam to spread into a wave packet
characterized by kT, is eithar very long or very
short is given respectively as ~ollows.
2 ~ 3~3
- 176 -
; w(~ - e~ ~
~_ _oO ( ~_ ~ W~ ) (24)
where In is the modifified sessel function of the
first kind; e ~ is the Deby -Waller factor;
~o=~(k xo)~
where Xo is the displacement of the nucleus rom
equilibrium in the o t~ normal mode.
~ r ~ ~c ) (25)
n ~ WO ) ~ (r/Y)
where Jn is the unmodified ~essel function of the
first kind.
For the first case, a short phonon relasation
time results in a Boltzman distributlon of ultrasonic
phonon states which produces the MossbauQr line shape
of Equation 24 where the original single line at
frequenCY Wt- ~t/ ~ has been partially split up into
an infinite number of side bands, each of relative
intensity e ~ spaced at intervals of nwo,
integer multiples of the ultrasonic frequency, from
the central, unshifted line.
For the second case of a long phonon rela~ation
time, the lattice phonons are in thermal equilibrium,
but the ultrasonic phonons are unable to interact
with the thermal phonons; thus, an ultrasonic mode is
superimposed to produce tho Mossbauer line shape of
Equation 25 where, again as or Equation 24, the
spoctrum splits into an infinite number of side
bands, in this case of relative intensity ~n( ~ )
g~3
- 177 -
spaced as for the former case at inter~als of nwo,
integer multiples of the ultrasonic frequency from
the central, unshifted line.
- Selective ~ossbauer absorption in a
predetermined region of space can be accomplished by
simultaneously administering a focused or collinated
ultrasonic beam and a gamma ray beam in such a
fa~hion that the beams intersect at the site of the
targat ttssue. The ormer beam e~ites a component
of ul~rasonic motion of the ~ossbaucr absorber nuclei
in the direction of the latter beam to create
absorption sidebands spaced at integar multiples of
the ultrasonic frequency from the central, unshifted
line a8 described by J. Mishory and D. I. Bolef,
Mossbauer E~fect ~Q~hQ~nlaqY, Irwin J. Gruverman,
Editor, Vol. 4, tl96a) pp. 1~-35, incorporated by
- reerence. The administered gamma rays are rssonant
with a sideband of energy which is not resonant with
any of the Mossbauer absorber nuclei in the
nonselected ti~sue along th~ gamma ray p~th: thus,
solectivity i~ achieved.
.'', ~1
The cross-section ~or absorptlon of resonant
radiation ~y Mossbauer nuclei are 108 t~mes that of
water; however, nonspeciflc scattering and absorption
occur~ for all g~m~2 radiation. The predominent
mechanism i~ the photoelectric effect and Compton
~cattering.
The photoelectric and Compton cross-section~ are
3~ summarizod in Table 10 which contains the mass energy
absorption coeficients in the ab~ence of the
Mo~sbauer effects. The equation for determining the
total do~e from gamma ray treatment and the depth of
ponetration of the photons appears in ~able 11.
~t~U~.~9
- 178 -
Table 11 and Table ln demonstrate the relationship
that photons of higher enerqy penetra~e deeper into
tissue. Since the di ferent Mossbauer sources
demonstrate a wide range o photon energies,
therapies can be designed to esploit this phenomenon
`~ to deliver the energy of the radiation to a selected
depth. Mossbauer sources o low energy gamma rays
which do not penetrate deeply ca~ he used to ~elivar
therapy superficially and spare deep tissue. For
esample, 5~Co is the source of a 14.4 KeV
Mossbauer gamma ray with a ma s energy tissue
absorption coeff icient of 1. 32 cm2~gm and would be
suitable for intraoperatiYe radiation and endoscopic
radiation using a miniturized source and mass drive
or ultrasonic drive. Breast, bowel, and pancreatic
r, c~ncer are candidates for the former; and lung cancer
i~ a candidate for the latter. Mossbauer sources o~
high energy gamma rays which ponetrate deeply can be
used to treat tumors that are not located
superficially. l~-Gd is the source of a 60 KeV
Mossbauer g~mma ray with a m~85 energy bone
absorption coeff~cient of .03 cm2~gm and represents
a suitable source for the treatment of primary and
m~tastatic bone cancer and deep solid tumors.
-- 17g --
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~u16~zu~
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. .
, ~ ~ V~ ,~, o U- ~ ~ o o o o o o o o o o o o o o o o o
.- ~ oo oo~aoo 50000 00000 oooo~a
~ ~ ~ V) _ O O 1~ 0 0 0 0 0 0 0 0 C~ ~ O O 0 9 0 0 0 0
_ ~ oo ooooo ooooo ooooo ooooo
~ o 8 1~ ~ ~ o. o o o o s s o ~ o o o o o o o o o~
U ~ c~ CIOO 0 O0 0 00000
r O ~ O O O O O O O O O O O O O O O O
ooooo 00000 00000 Ci0000
~~ ~ ~ ~ O~ ~ ~ ~ O O O 0 0~ 0~ 0 0 0 0 0 0 0 0 0 0 0
io 00000 00000 00000 00000
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39
- 180 -
-'
Table 12 below provides additional information
and clarification of Fig. 11, previously discussed
above.
TABLE 12
27-CO~ALT-57
HALFLIFE = 270.9 DAYS 24 MAY 77
DECAY MODEtS): EC
y(i) E(i)
RADIATION (Bq-s)~l (MeV) y(i)~E(i)
y 1 9.19E-02 1.441E-02 1.32E-03
ce-K, y 1 7.13E-01 7.301E-03 5.20E-03
ce-Ll, y 1 6.80E-02 1.3s7E-02 9.22E-04
ce-L2, y 1 4.20E-03 1.369E-02 5.7SE-05
ce-L3, y 1 1.69E-03 1.370E-02 2.31E-05
y 2 8.56E-01 1.221E-01 1.04E-01
ce-R, y 2 1.84E-02 1.150E-01 2.12E-03
ce-Ll, y 2 1.73E-03 1.212E-01 2.10E-04
r 3 1.06E-01 1.365E-01 1.45E-02
ce-K, y 3 1.43E-02 1.294E-01 1.84E-03
Ce-Ll~ y 3 1.27E-03 1.356E-01 1.73E-04
y 9 1.60E-03 6.920E-01 l.llE-03
Kal X-ray ~.34E-01 6.404E-03 2.14E-03
K~2 X-ray 1.69E-01 6.391E-03 1.08E-03
XBl X-ray 4.51E-02 7.058E-03 3.19E-04
RB3 X-ray 2.29E-02 7.058E-03 1.61E-04
Auger-K~L 8.54E-01 5.574E-03~ 4.76E-03
Auger-KLX 2.04E-01 6.302E-03~ 1.29E-08
Auger-KXY 1.79E-02 7.000E-03~ 1.25E-04
Auger-LMM 2.43E 00 6.703E-04~ 1.63E-03
Auger-LMX 1.54E-01 7.067E-04~ 1.09E-04
Aug2r-MXY 5.33E 00 2.232E-05~ l.l9E-04
LISTED X, y and y~ RADIATIONS 1.25E-01
OMI m D XO y and y~ RADIATIONS~ 1 57E-04
LTSTED ~, ce AND Auger RADIATIONS 1 86E-02
OMITTED B, ce AND Auger RADIATIONS~ 4.08E-05
LISTED RADIATIONS 1 44E-01
- OMI m D RADIATIONS~ 1 98E-04
AVERAGE ENERGY ~MeV)
EACH OMITTED TRANSITION CONTaI~UTES c0.100% TO
~y(i)sE(i) IN ITS CATEGORY.
IRON-57 DAUGHTER IS STA~LE.
3~3
- 181 -
' '
Table 1~ below provides additional information
and clarification of Fig. 12, previously discussed
above.
TABLE 13
50 TIN-119M
H~LFLIFE = 293 D~YS 17 MAR 7 9
DEC~Y MODE~S): IT
y~i) E(i)
RADIATION (Bq-s)-l (MeV) y(i)zE(i)
y 1 1.63E-01 2.387E-02 3.89E-03
ce-Ll, y 1 6.12E-01 1.941E-02 l.l9E-02
ce-L2, y 1 5.06E-02 1.971E-02 9.98E-04
ce-L3, y 1 1.41E-02 1.994E-02 2.81E-04
ce-M, y 1 1.32E-01 2.316E-02~ 3.06E-03
ce-N+, y 1 2.85E-02 2.387E-02% 6.80E-04
y 2 1.94E-04 6.566E-02 1.27E-05
ce-K, y 2 3.22E-01 3.646E-02 1.17E-02
ce-Ll, y 2 1.53E-01 6.120E-02 9.34E-03
ce-L2, y 2 3.35E-02 6.150E-02 2.06E-03
ce-L3, y 2 3~37E-01 6.173E-02 2.08E-02
ce-M, y 2 1.24E-01 6.495E-02~ 8.04E-03
ce-N~, y 2 3.10E-02 6.566E-02~ 2.04E-03
K~l X-ray 1.48E-01 2.527E-02 3.74E-03
X~2 X-ray 7.90E-02 2.504E-02 1.98E-03
XBl X-ray 2.74E-02 2.849E-02 7.80E-04
KB2 X-ray 8.14E-03 2.911E-~2 2.37E-04
XB3 X-ray 1.41E-02 2.844E-02 4.02E-04
La X-ray 5.51E-02 3.443E-03~ 1.90E-04
L~ X-ray 5.06E-02 3.737E-03~ 1.89E-04
L~ X-ray 7.36E-03 4.309E-03~ 3.17E-05
Auger-KL~ 3.03E-02 2.082E-02~ 6.3lE-04
Auger-KLX 1.34E-02 2.429E-02~ 3.25E-04
Auger-LMM 8.97E-01 2.808E-03* 2.52E-03
Auqer-LMX 4.31E-01 3.488E-03~ 1.50E-03
Augor-LXY 5.68E-02 3.947E-03~ 2.24E-04
- Augor-MXY 2.64E 00 5.938E-04* 1.57E-03
LI8TED X, y and y~ RADIATIONS l.lSE-02
OMITTED X, r and y~ RADIATIONS~ 1.4~E-05
LISTED ~, ce AND Auger RADIATIONS 7.77E-02
OMITTED ~, c~ AND Auger RADIATIONS*~ 7.14E-05
LI8TED RADIATIONS 8.91E-02
OMITTED RADIATIONS~ 8.55E-05
AVERAGE ENERGY (MeV)
*~ EACH OMITTED T~ANSITION CONTRIBUTES <0.100% TO
~y~i)~E(i) IN ITS CATEGORY.
TIN-ll9 DAUGHTER IS STABLE.
~0~ 3~
- 182 -
Table 14 below provides additional information
and clarification of Fig. 13, previously discussed
above.
TA8LE 14
50-TIN-121M
HALFLIFE = 55 YEARS 17 MAR 79
DECAY MODE(S) ~ , IT
RADIATION (BqY())l (~v3 y(~ E(i)
B- 1 2.24E-01 1.207E-01~ 2.70E-02
y 1 l.B5E-02 3.715E-02 6.87E-04
ce-K, y 1 1.76E-01 6.659E-03 1.17E-03
ce-Ll, y 1 2.08E-02 3.245E-02 6.77E-04
c~-L~, y 1 1.64E-03 3.277E-02 5.38E-05
ce-M, y 1 4.51E-03 3.638E-02~ 1 64E-04
ce-N~, y 1 1.06E-03 3.715E-02~ 3 92E-05
Kal X-ray 8.15E-02 2.636E-02 2.15E-03
K~2 X-ray 4.36E-02 2.611E-02 1 14E-03
KBl X-ray 1.52E-02 2.973E-02 4 53E-04
KB2 X-ray 4.60E-03 3.040E-02 1.40E-04
KB3 X-ray 7.86E-03 2.968E-02 2.33E-04
La X-ray 6.29E-03 3.604E-03* 2.27E-05
LB X-ray 5.77E-03 3.901E-03~ 2.25E-05
Auger-KL~ 1.56E-02 2.167E-02* 3.37E-04
Auger-KLK 6.98E-03 2.531E-02* 1.77E-04
Auger-LMM l.llE-01 2.960~-03* 3.28E-04
Auger-LMX 5.48E-02 3.685E-03* 2.02E-04
Aug~r-MXY 3.25E-01 6.490E-04~ 2.11E-04
ce-L3, y 1 4.86E-01 2.361E-03 1.15E-03
cQ-M, y 1 2.26E-01 5.576E-03* 1.26E-03
c~-N~, y 1 5.80E-02 6.290E-03* 3.65E-04
La X-ray 2.41E-02 3.443E-03* 8.2iE-05
LB X-ray 3.85E-03 3.8B9E-03* 1.50E-05
Auger-LMM 3.00E-01 2.736E-03~ 8.21E-04
Auger-LMX 1.44E-01 3.414E-03* 4.9lE-04
Auger-LXY l.91E-02 3.875E-03R 7.41E-05
Auger-MXY 9.9SE-01 6.049E-04* 6.02E-04
LI8TED X, y and y~ RADIATIONS 4.94E-03
OMITTED X, y and y~ RADIAT~ONS*~ 1.09E-05
LISTED B, ce AND Auger RADIATIONS 3.52E-02
OMITTED B, ce AND Auger RADIATIONS~ 9.52E-05
~ISTED RADIATIONS 4.01E-02
OMITTED RADIATIONS*~ 1.06E-04
AVERAGE ENERGY (MeV)
EACH OMITTED TRANSITION CONTRIBUTES <0.100% TO
~y(~)~Eti) IN ITS CATEGORY.
ANTIMONY-121 DAUGHTER, YIELD 2.24E-01, IS STA~LE.
TIN-121 DAUGHTER, YIELD 7.76E-01, IS RADIOACTIVE.
~50~!3
183 -
Table 15 below provides additional information
and clari~ication of Fig. 19, previously discussed
above.
TABLE 15
53 - IODINE - 125
HALFLIFE = 60.14 DAYS 17 JUNE 78
DECAY MODE~S): EC
y(i) E(i)
RADIATION (Bq-s) 1 (MeV) y~i)xE(i)
y 1 6.67E-02 3.549E-02 2.37E-03
ce-K, y 1 8.03E-01 3.678E-03 2.95E-03
ce-Ll, y 1 9.52E-02 3.055E-02 2.91E-03
ce-L2, y 1 7.64E-03 3.088E-02 2.36E-04
ce L3, y 1 l.91E-03 3.115E-02 5.96E-05
ce-M, y 1 2.09E-02 3.467E-02~ 7.25E-04
ce-N~, y 1 4.96E-03 3.549E-02~ 1.76E-04
K~l X-ray 7.41E-01 2.747E-02 2.04E-02
K~2 X-ray 3.98E-01 2.720E-02 1.08E-02
KBl X-ray 1.40E-01 3.100E-02 4.34E-03
KB2 X-ray 4.30E-02 3.171E-02 1.36E-03
RB3 X-ray 7.20E-02 3.094E-02 2.23E-03
RB5 X-ray 1.44E-03 3.124E-02 4.51E-05
La X-ray 6.14E-02 3.768E-03~ 2.31E-04
LB X-ray 5.93E-02 4.092E-03* 2.43E-04
Augar-K~L 1.32E-01 2.254E-02~ 2.97E-03
Auger-K~X 5.97E-02 2.63SE-02~ 1.57E-03
Auger-KXY 7.95E-03 3.013E-02~ 2.40E-04
Auqer-LMM 1.01E 003.086E-03s 3.11E-03
Auger-LMX 5.17E-01 3.855E-03~ l.99E-03
Auger-LXY 7.33E-02 4.386E-03* 3.21E-04
Augor-MXY 2.99E 006.989E-04~ 2.09E-03
6~22E-01 5.577E-05~ 3.47E-05
~I8TED X, y and y~ ~ADIATIONS 4.20E-02
O~ITTED X, y and y~ RADIATIONS*~ 4.58E-05
LISTED B, ce AND Auger RADIATIONS l.g4E-02
~ISTED RADIATION8 6.14E-02
OMITTED RADIATIONS** 4.5aE-05
* AVERAGE ENERGY (MeV)
*~ EACH OMITTED TRANSITION CONTRI~UTES <0.100~ TO
~y(i)~E(i) IN ITS CATEGORY.
TELLURIUM-125 DAUGHTER IS STA~LE.
,.~,
:,
- 184 -
.
Modi~ications and substitutions of the
com~ounds, pharmaceuticals, apparatus, methods,
systems, and process steps made by one skilled in the
ar~ i5 within the scope of the present invention~
Moreov~r, although Mossbauer absorption includes the
absorption of gamma rays, the scope o the present
invention include~ in the tsrm Mossbauer absorption
the absorption of electromagnetic en~rgy at narrow
ab30rption llnes or regions by s~le~ted materials.
l~ Furthefmore, th~ terms wavelength, energ~ and
frequency ~l~ed herein according to the present
invention provide characteristics related according
to the formula
E = hv - hc~ (26)
Thus the scope of ths present invention ig not
limited e~cept according to thc claim~ which follow.
',
