U.S. patent application number 11/124654 was filed with the patent office on 2005-09-22 for high energy phototherapeutic agents.
This patent application is currently assigned to Xantech Pharmaceuticals, Inc.. Invention is credited to Dees, H. Craig, Scott, Timothy, Smolik, John T., Wachter, Eric A..
Application Number | 20050207976 11/124654 |
Document ID | / |
Family ID | 22808515 |
Filed Date | 2005-09-22 |
United States Patent
Application |
20050207976 |
Kind Code |
A1 |
Dees, H. Craig ; et
al. |
September 22, 2005 |
High energy phototherapeutic agents
Abstract
A high energy phototherapeutic agents or radiosensitizer agent
comprised of a halogenated xanthene, or an agent that exhibits a
preference for concentration in biologically sensitive structures
in diseased tissue, and methods of treating and imaging using
radiosensitizer agents in diseased tissue.
Inventors: |
Dees, H. Craig; (Knoxville,
TN) ; Scott, Timothy; (Knoxville, TN) ;
Smolik, John T.; (Loudon, TN) ; Wachter, Eric A.;
(Oak Ridge, TN) |
Correspondence
Address: |
COOK, ALEX, MCFARRON, MANZO, CUMMINGS & MEHLER LTD
SUITE 2850
200 WEST ADAMS STREET
CHICAGO
IL
60606
US
|
Assignee: |
Xantech Pharmaceuticals,
Inc.
|
Family ID: |
22808515 |
Appl. No.: |
11/124654 |
Filed: |
May 9, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11124654 |
May 9, 2005 |
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09382622 |
Aug 25, 1999 |
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09382622 |
Aug 25, 1999 |
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09216787 |
Dec 21, 1998 |
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6331286 |
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Current U.S.
Class: |
424/1.49 ;
424/1.69; 424/1.73; 514/1.2; 514/19.3; 514/44R |
Current CPC
Class: |
Y10S 436/819 20130101;
A61K 41/0038 20130101; A61P 43/00 20180101; A61K 49/0433 20130101;
Y10S 436/813 20130101; A61P 35/00 20180101 |
Class at
Publication: |
424/001.49 ;
514/012; 514/044; 424/001.69; 424/001.73 |
International
Class: |
A61K 051/00 |
Claims
1-53. (canceled)
54. A combination for treatment of cancer or tumors, said
combination consisting of a radiosensitizer agent and applied
ionizing radiation, said radiosensitizer agent comprising a
halogenated xanthene, wherein said radiosensitizer agent interacts
with said applied ionizing radiation upon application of said
applied ionizing radiation to said cancer or tumors to enhance the
therapeutic efficacy of said applied ionizing radiation, wherein
said halogenated xanthene is not contained in an immuno-liposome,
and wherein said halogenated xanthene does not contain a
radioisotope.
55. The combination of claim 54 wherein said halogenated xanthene
comprises Rose Bengal.
56. The combination of claim 54 wherein said halogenated xanthene
comprises 4,5,6,7-Tetrabromoerythrosin.
57. The combination of claim 54 wherein said halogenated xanthene
includes as a functional derivative at least one targeting moiety
selected from the group consisting of deoxyribonucleic acid (DNA),
ribonucleic acid (RNA), amino acids, proteins, antibodies, ligands,
haptens, carbohydrate receptors or complexing agents, lipid
receptors or complexing agents, protein receptors or complexing
agents, chelators, short- or long-chain aliphatic or aromatic
hydrocarbons, aldehydes, ketones, alcohols, esters, amides, amines,
nitriles, and azides.
58. The combination of claim 54 wherein said halogenated xanthene
includes at least one halogen selected from the group consisting of
iodine and bromine.
59. The combination of claim 54 wherein said halogenated xanthene
is selected from the group consisting of Phloxine B, Erythrosin B
and Eosin Y.
60. The combination of claim 54 wherein at least one biological
targeting moiety is attached to said halogenated xanthene to
enhance targeting of said halogenated xanthene to biologically
sensitive structures of said cancer or tumors.
61. The combination of claim 54 wherein at least one chemical
targeting moiety is attached to said halogenated xanthene to
enhance targeting of said halogenated xanthene to biologically
sensitive structures of said cancer or tumors.
62. The combination of claim 54 wherein said ionizing radiation is
approximately greater than or equal to 1 keV and less than or equal
to approximately 1000 MeV.
63. The combination of claim 54 wherein said halogenated xanthene
includes as a functional derivative at least one targeting moiety
selected from the group consisting of hydrophilic and hydrophobic
moieties.
64. The combination of claim 54 wherein said ionizing radiation
comprises x-rays.
65. The combination of claim 64 wherein said x-rays have an energy
between 30 kiloelectron volts and 1000 megaelectron volts.
66. A combination for treatment of cancer or tumors, said
combination consisting of a radiosensitizer agent and applied
ionizing radiation, wherein said radiosensitizer agent comprises a
halogenated xanthene and said applied ionizing radiation has an
energy greater than 1 keV and less than 1000 MeV, and wherein said
halogenated xanthene is not contained in an immuno-liposome.
67. The combination of claim 66 wherein said halogenated xanthene
comprises Rose Bengal.
68. The combination of claim 66 wherein said halogenated xanthene
includes as a functional derivative at least one targeting moiety
selected from the group consisting of deoxyribonucleic acid (DNA),
ribonucleic acid (RNA), amino acids, proteins, antibodies, ligands,
haptens, carbohydrate receptors or complexing agents, lipid
receptors or complexing agents, protein receptors or complexing
agents, chelators, short- or long-chain aliphatic or aromatic
hydrocarbons, aldehydes, ketones, alcohols, esters, amides, amines,
nitriles, and azides.
69. The combination of claim 66 wherein said halogenated xanthene
also is an imaging contrast agent.
70. A combination for treatment of cancer or tumors using
radiosensitization, said combination consisting of a
radiosensitizer agent and applied ionizing radiation, said
radiosensitizer agent comprising a halogenated xanthene, wherein
said applied ionizing radiation has an energy greater than 1 keV
and less than 1000 MeV, and wherein said halogenated xanthene is
not contained in an immuno-liposome.
71. In combination, a radiosensitizer agent and applied ionizing
radiation for treatment of cancer or tumors, said radiosensitizer
agent comprising a halogenated xanthene and said applied ionizing
radiation comprising x-rays having an energy greater than 30 keV,
wherein said radiosensitizer agent is activated by said x-rays, and
wherein said halogenated xanthene is not contained in an
immuno-liposome.
72. The combination of claim 71 wherein said halogenated xanthene
comprises Rose Bengal.
73. The combination of claim 72 wherein said halogenated xanthene
includes as a functional derivative at least one targeting moiety
selected from the group consisting of deoxyribonucleic acid (DNA),
ribonucleic acid (RNA), amino acids, proteins, antibodies, ligands,
haptens, carbohydrate receptors or complexing agents, lipid
receptors or complexing agents, protein receptors or complexing
agents, chelators, short- or long-chain aliphatic or aromatic
hydrocarbons, aldehydes, ketones, alcohols, esters, amides, amines,
nitrites, and azides.
74. In combination, a radiosensitizer agent and applied ionizing
radiation for treatment of cancer or tumors using
radiosensitization, said radiosensitizer agent comprising a
halogenated xanthene, wherein said applied ionizing radiation has
an energy greater than 1 keV and less than 1000 MeV, and wherein
said halogenated xanthene is not contained in an
immuno-liposome.
75. A halogenated xanthene and applied ionizing radiation for
treatment of cancer or tumors using radiosensitization, wherein
said applied ionizing radiation has an energy greater than 1 keV
and less than 1000 MeV, and wherein said halogenated xanthene is
not contained in an immuno-liposome.
Description
BACKGROUND OF THE INVENTION
[0001] The present invention is directed to high energy
phototherapeutic agents, or specifically to radiosensitizing and
methods of treating and imaging using such phototherapeutic or
radiosensitizer agents. More specifically, the treating and imaging
is of diseased tissue, such as tumors, particularly cancerous
tumors.
[0002] Diseased tissue or tumors, such as those for cancer, are
often treated using ionizing radiation, in a process known as
radiation therapy.
[0003] Radiation therapy (which typically uses electromagnetic
radiation with energies of 1 keV or higher) for cancer typically
works by attacking rapidly growing cells with highly penetrating
ionizing radiation. Use of such radiation is attractive due to its
ability to penetrate deeply into tissue, especially when diseased
tissue is, or is located within, bone or other dense or opaque
structures. Unfortunately, using rapid growth as the sole targeting
criterion does not limit the effects of such treatment to cancer
cells.
[0004] As a result, improvements have been made in the methods for
delivery of the ionizing radiation to the site of the cancerous
tumor so as to limit the effects of such radiation to the general
area of the cancerous tumor. However, since healthy tissue and
cancerous tissue typically have a similar biological response to
radiation, a need exists to improve the potency of (or biological
response to) the delivered radiation within and in the vicinity of
the tumor, while not affecting the surrounding healthy tissue.
[0005] As an alternative to the use of ionizing radiation,
photodynamic therapy (PDT) has been developed and shows
considerable promise for treatment of a variety of cancers.
Photodynamic therapy is the combination of a photosensitive agent
with site-specific illumination (using non-ionizing, optical
radiation) to produce a therapeutic response in diseased tissue,
such as a tumor. In PDT, a preferential concentration of
photosensitizer is to be located in the diseased tissue, either
through natural processes or via localized application, and not in
the healthy surrounding tissue. This provides an additional level
of tissue specificity relative to that achievable through standard
radiation therapy since PDT is effective only when a
photosensitizer is present in tissue. As a result, damage to
surrounding, healthy tissue can be avoided by controlling the
distribution of agent. Unfortunately, when using conventional
methods for the illumination step in PDT (1) the light required for
such treatment is unable to penetrate deeply into tissue, and (2)
the physician has minimal spatial control of the treatment site.
This is particularly troublesome whenever the diseased tissue or
tumor is deeply seated or located within bone or other opaque
structures. Some of the inventors of the present invention have
been able to resolve many of these problems for PDT, as shown in
commonly-assigned U.S. Pat. No. 5,829,448.
[0006] Others, however, have focused their efforts on developing
agents that are sensitized or activated by the ionizing radiation
mentioned above. Potentially, the use of such radiation would
enable treatment of more deeply seated diseased tissue than that
possible with optical radiation. The agents used with such
radiation are known as radiosensitizers. It is also desirable to
achieve preferential concentration of the radiosensitizer in the
diseased tissue, either through natural processes or via localized
application, so as to provide additional specificity relative to
that achievable through standard radiation therapy. The desired
result is for radiation to become more efficacious when the
radiosensitizer is present in tissue, so that less radiation is
needed to treat the lesion tumor or other diseased tissue, and
accordingly, potential damage to surrounding healthy tissue,
resulting from collateral exposure to the radiation, is reduced.
Hence, safety and efficacy would then be improved.
[0007] The ultimate success or failure of the radiosensitizer
approach depends on: (1) therapeutic performance of agents, and (2)
disease specificity in the site of activation. Currently used
agents and targeting approaches, however, have had unacceptable
results in each of these categories.
[0008] The therapeutic performance of a radiosensitizer is
primarily a function of enhanced absorption of the applied
radiation dose in sensitized tissues relative to that in
non-sensitized tissues. This differential absorption is commonly
effected by use of agents having a high absorption cross-section
for a particular type of radiation (such as x-rays). For example,
metal or halogen atoms are often used, either in atomic form or
incorporated into a molecular carrier, due to their high x-ray
cross-section. Absorption of x-rays by such atoms appears to lead
to secondary radiative emissions, ionization, and other chemical or
physical processes that increase the localized cytotoxicity of the
applied energy (i.e., radiation-induced cell death, or "light
cytotoxicity").
[0009] However, a high light cytotoxicity is not enough to make an
agent an acceptable agent. The agents must also have a negligible
effect when energy is not applied (i.e., have a low toxicity in the
absence of radiation, or "dark cytotoxicity"). Unfortunately, many
agents presently under investigation as radiosensitizers have the
disadvantage of either: (a) a relatively high dark cytotoxicity or
(b) a low light (cytotoxicity)-to-dark cytotoxicity ratio which
limits their effectiveness and acceptability. Agents having a high
light-to-dark cytotoxicity ratio are desirable because they (1) can
be safely used over a range of dosages, (2) win exhibit improved
efficacy at the treatment site (due to the compatibility with use
at higher dosages as a consequence of their relative safety), and
(3) will be better tolerated throughout the patient's body.
[0010] An additional problem with many current radiosensitizers is
that the agent does not achieve significant preferential
concentration in tumors. Specifically, most radiosensitizer
targeting has been based on physical targeting, such as diffusion
into tumors through leaky neurovasculature, which ultimately
succeed or fail based on permeability of the tumor to agents that
are aqueously soluble or are in a suspension formulation. As a
result, large doses of the agent typically need to be administered,
either locally or systemically, so as to saturate all tissues,
hopefully reaching a therapeutic level in the desired treatment
region or target. After such agent administration, a patient has to
wait a clearance time of hours to days to allow excess agent to
hopefully clear from healthy living tissues surrounding the desired
treatment site. Thereafter, irradiation of residual agent at the
treatment site hopefully produces the desired cytotoxic effect in
the diseased tissue. This approach may unfortunately also damage
healthy surrounding tissue by undesired but unavoidable activation
of residual agent still present in the healthy surrounding tissue.
One approach to solving this problem is to couple the
radiosensitizer with a moiety capable of providing improved
biotargetting of the diseased tissue. This, however, has proven to
be very difficult to achieve.
[0011] It would also be highly desirable if the radiosensitizer
could be used to improve identification of target size, location
and depth so that the therapeutic radiation could be more precisely
delivered to the target, such as a cancerous tumor. Combined
diagnostic use (as a contrast agent) and therapeutic use (as a
radiosensitizer) of the agent would reduce risk to the patient by
(1) reducing the number of required procedures necessary for
diagnosis and treatment, (2) reducing the overall diagnosis and
treatment time, and (3) reducing cost.
[0012] Accordingly, one object of the present invention is to
develop new radiosensitizers that have one or more of the following
characteristics: (1) improved light-to-dark cytotoxicity ratio; (2)
improved accumulation of agent into diseased tissue with strong
contrast between diseased and healthy tissue; (3) rapid clearance
from normal tissue; and (4) capability of combined imaging and
therapy. Further desirable characteristics include low agent cost,
and significant regulatory history (so as to facilitate acceptance
by the regulatory and medical communities).
SUMMARY OF THE INVENTION
[0013] The present invention is directed to a radiosensitizer agent
for treatment of diseased tissue using radiosensitization or
ionizing radiation comprising a halogenated xanthene. Preferably,
the halogenated xanthene is Rose Bengal or its derivative.
[0014] In a further embodiment of the present invention, the
radiosensitizer agent also acts as an imaging contrast agent.
[0015] The present invention is also directed to a radiosensitizer
agent for treatment of diseased tissue using radiosensitization or
ionizing radiation wherein the agent exhibits a preference for
concentration in biologically sensitive structures in tissue, such
as, for example, cellular membranes. Preferably, the agent
biologically or chemically targets the biologically sensitive
structures.
[0016] Further, the present invention is directed to a method for
treating diseased tissue.
[0017] One embodiment of the method of the present invention
includes the steps of administering a radiosensitizer agent,
preferably a halogenated xanthene, a portion of radiosensitizer
agent being retained in diseased tissue; and treating the diseased
tissue with x-rays or other ionizing radiation to activate the
radiosensitizer agent in the diseased tissue.
[0018] A further embodiment of the method of the present invention
includes the step of imaging a patient using the radiosensitizer
agent to identify the diseased tissue.
BRIEF DESCRIPTION OF THE DRAWINGS
[0019] FIG. 1a is an illustration of the chemical structure of Rose
Bengal;
[0020] FIG. 1b is an illustration of the chemical structure of a
halogenated xanthene;
[0021] FIG. 2 illustrates the CAT scan image of test tubes of Rose
Bengal, standard x-ray contrast agents and a control;
[0022] FIG. 3 illustrates a CAT scan of a range of concentrations
of the solutions of FIG. 3;
[0023] FIG. 4 is a graph of energy versus x-ray cross-section for
halogens.
DETAILED DESCRIPTION OF THE PRESENTLY PREFERRED EMBODIMENTS
[0024] The present invention is directed to agents that can
efficiently interact with x-rays or other types of ionizing
radiation to produce a beneficial biological response and to
methods of treatment and imaging using such agents.
[0025] The inventors of the present invention have discovered that
radio dense agents, such as the halogenated xanthenes discussed
infra, which exhibit a preference for concentration in cellular
membranes and other key components and structures of diseased
tissue, will exhibit additional therapeutic dose enhancement over
that possible with previously known agents or enhancement
mechanisms. This additional dose enhancement is a consequence of
increased radiosensitization yield of such agents owing to improved
proximity of such agents, upon interaction with diseased tissue, to
sensitive structures during irradiation and subsequent
radiosensitization. Specifically, most radiosensitizers function by
absorbing highly-penetrating energy (which in itself has little
direct interaction with tissue), and then releasing this energy in
a less-penetrating, more cytotoxic form (such as lower-energy
re-emission) that is capable of interacting primarily only with
proximal, biologically-sensitive structures or materials (such as
cellular membranes and genetic material).
[0026] Thus, any radiodense agent, such as halogenated xanthenes,
that exhibits chemical or biological targeting to such
biologically-sensitive structures or materials, and which thereby
becomes substantially concentrated in areas in physical proximity
to such structures or materials, will increase the overall
efficiency of radiosensitization (i.e. conversion of high-energy
stimulating excitation into localized cytotoxic effects). This
yield enhancement results from the increased probability that
proximally-released energy will interact favorably with the
sensitive target (before annihilating or otherwise dissipating in
an inefficacious manner) whenever the agent responsible for such
re-emission is concentrated as close as possible to such a target.
Stated in simple terms, the released energy, having a short mean
free path, will have a higher probability of interacting with the
target if it is emitted from an agent located closer to the
target.
[0027] Such approaches to radiosensitization enhancement are not
taught in the prior art, which are based primarily on
permeability-based targeting. In contrast, targeting as taught by
the present invention uses the superior approach based on chemical
or biological targeting. This type of targeting can be effected by
chemical partitioning of the agent at, near or into the target (for
example, using an agent that partitions into cell walls, such as
Rose Bengal discussed infra, the chemical structure of which is
illustrated in FIG. 1a), by controlled agent delivery at, near or
into the target (for example by encapsulation of an agent, such as
Rose Bengal, into a delivery vehicle, such as a micelle,
nanoparticle, or liposome, that interacts preferentially with a
target site, such as cell walls, and may adhere, fuse, combine, or
otherwise interact in such a way that agent is delivered to the
target), or by physically increasing local concentration of agent
at, near or into the target, for example by localized delivery via
injection, flooding, or spraying.
[0028] Preferably, these agents have a large x-ray cross-section, a
high light-to-dark cytotoxicity ratio, a preference for
accumulation in diseased tissue, low agent cost, rapid clearance
from normal tissue, and a significant regulatory history (so as to
facilitate acceptance by the regulatory and medical
communities).
[0029] Applicants have discovered a class of agents that fits this
criteria and is preferably used in the present invention. These
agents are referred to as halogenated xanthenes and are illustrated
in FIG. 1b, where the symbols X, Y, and Z represent various
elements present at the designated positions, and the symbols
R.sup.1 and R.sup.2 represent various functionalities present at
the designated positions. Chemical and physical properties (such as
the chemical constituents at positions X, Y, and Z and the
functionalities R.sup.1 and R.sup.2, along with molecular weight)
of representative halogenated xanthenes are summarized in attached
Table 1. While many of the halogenated xanthenes are highly soluble
in aqueous solution, in general all demonstrate a preference for
selective partitioning into hydrophobic environments, such as
within cell membranes.
[0030] In general, halogenated xanthenes are characterized by a low
dark cytotoxicity and chemical properties that are substantially
unaffected by the local chemical environment or the attachment of
functional derivatives at positions R.sup.1 and R.sup.2. Moreover,
the halogenated xanthenes will target some tumors or other diseased
tissues based on their inherent selective partitioning
properties.
[0031] A specific example of a halogenated xanthene is Rose Bengal
(4,5,6,7-tetrachloro-2',4',5',7'-tetraiodofluorescein; see 10 in
FIG. 1a). In particular, Rose Bengal has been found to accumulate
preferentially in (i.e. target) some tumors and other diseased
tissues. Moreover, Rose Bengal has other desirable characteristics
such as a negligible dark cytotoxicity, relatively low cost, the
ability to clear rapidly from the body, and a partially established
regulatory history. Furthermore, the inventors have found that the
special chemical properties of Rose Bengal allow it to be dissolved
in aqueous solution at high concentrations while retaining a
significant preference for hydrophobic environments, such as within
cell membranes.
[0032] The present inventors have also discovered that the facility
with which the halogenated xanthenes target specific tissues or
other sites can be optimized by attachment of specific functional
derivatives at positions R.sup.1 and R.sup.2, so as to change the
chemical partitioning or biological activity of the agent. For
example, attachment of one targeting moiety or more at positions
R.sup.1 or R.sup.2 can be used to improve targeting to specific
tissues, such as cancerous tumor tissues or sites of localized
infection. These targeting moieties include DNA, RNA, amino acids,
proteins, antibodies, ligands, haptens, carbohydrate receptors or
complexing agents, lipid receptors or complexing agents, protein
receptors or complexing agents, chelators, encapsulating vehicles,
short- or long-chain aliphatic or aromatic hydrocarbons, including
those containing aldehydes, ketones, alcohols, esters, amides,
amines, nitrites, azides, or other hydrophilic or hydrophobic
moieties.
[0033] An example of this feature would be to combine Rose Bengal
with a lipid (at position R.sup.1, via esterification, so as to
increase the lipophilicity of Rose Bengal, and thereby modify its
targeting properties in a patient. Such a modified agent could be
administered directly as a micelle suspension, or delivered in
conjunction with a delivery vehicle, such as a surfactant, and
would exhibit increased targeting to tumor cells. Suitable
formulations of such an agent include topical creams and lotions,
and liquids for intravenous or parenteral injection.
[0034] FIG. 4 demonstrates that strong absorption for the halogens
of the halogenated xanthenes occurs well below the energies used
for standard diagnostic or therapeutic x-ray devices, which
generally use energies greater than 30 keV. In fact, the halogen
content of the halogenated xanthenes makes this class of agent
potent x-ray absorbers, and thus highly suitable as
radiosensitizers. Further, since x-ray cross-section increases
substantially in the order F<C1<Br<I, it is preferred that
those halogenated xanthenes with a large content of I or Br be used
for x-ray sensitization. Furthermore, tests indicate that the
presence of I or Br yields enhanced sensitization relative to that
possible with other halogens. Therefore, as shown in Table 1,
Tetrabromoerythrosin, Rose Bengal, Phloxine B, Erythrosin B, and
Eosin Y have larger x-ray cross-sections than Solvent Red or Eosin
B as a consequence of respective differences in halogen content,
and thereby are preferred for use as x-ray sensitizing agents. More
preferably, the high iodine content of Rose Bengal and its
derivatives and the additional bromine substitution of
4,5,6,7-Tetrabromoerythrosin and its derivatives, makes these
agents the most preferred x-ray sensitizing agents of this
class.
[0035] Accordingly, in a preferred embodiment of the present
invention, at least one halogenated xanthene is used as an x-ray
sensitizer or radiosensitizer agent for treatment of diseased
tissue using radiosensitization. Prior to radiosensitization, the
agent can be administered orally, systemically (e.g. by an
injection), or topically, in a manner well known in the art. In a
further preferred embodiment of the present invention, Rose Bengal
or its derivatives or 4,5,6,7-Tetrabromoerythrosin or its
derivatives is the radiosensitizer agent. It is also preferred that
x-rays or other ionizing radiation with energy
.gtoreq.approximately 1 keV and <1000 MeV be used to activate
the agent. Preferably, the agent is activated using x-rays having
an energy in excess of 30 keV.
[0036] Applicants have also discovered that halogenated xanthenes
can be used as an imaging contrast agent for x-ray or other
ionizing radiation imaging, such as CAT scan, fluorography or other
related procedures. In particular, the inventors have discovered
that halogenated xanthenes are particularly proficient as imaging
contrast agents because of their large x-ray cross-sections and
because their chemical structure, which has a high electron density
due to their significant halogen content, renders them opaque to
x-rays or other ionizing radiation used for imaging. For example,
Rose Bengal is highly opaque to the x-rays used for CAT scan or
normal x-ray imaging. FIGS. 2 and 3 illustrate the opaqueness of
Rose Bengal versus standard x-ray contrast agents and a control.
These figures are drawings of actual pictures of experiments done
by the inventors of the present invention. For example, the CAT
scan image of test tubes containing various solutions shown in FIG.
2 demonstrates that iodine (350 mgI/mL in aqueous base), Rose
Bengal (225 mg halogen/mL in saline), and Omnipaque.TM. (350 mgI/mL
Iohexol) have similar x-ray densities. Furthermore, these densities
are dramatically greater than that of a control (saline). A CAT
scan image of various dilutions of these same solutions (held in
wells in a 96-well sample plate) illustrated in the drawing in FIG.
3 further demonstrates that Rose Bengal shows comparable response
to that of the standard x-ray contrast agents across a range of
concentrations.
[0037] Accordingly, it is a further preferred embodiment of the
present invention to use at least one halogenated xanthene agent as
an imaging contrast agent for x-ray or ionization radiation based
imaging and detection of diseased tissue, and then treat the
detected diseased tissue by radiosensitization of the residual
agent present in such tissue.
[0038] This description has been offered for illustrative purposes
only and is not intended to limit the invention of this
application, which is defined in the claims below. For example, it
will be clear to those of ordinary skill in the art that the
targeting described herein for the specific example of the
halogenated xanthenes can be adapted or otherwise applied to other
radiodense materials, including conventional radiosensitizers. What
is claimed as new and desired to be protected by Letters Patent is
set forth in the appended claims.
1TABLE I Physical Properties of Example Halogenated Xanthenes:
Substitution Compound X Y Z R.sup.1 R.sup.2 MW (g) Fluorescein H H
H Na Na 376 4',5'-Dichlorofluorescein Cl H H Na Na 445
2',7'-Dichlorofluoresce- in H Cl H Na Na 445
4,5,6,7-Tetrachlorofluorescein H H Cl H H 470 2',4',5',7'- Cl Cl H
Na Na 514 Tetrachlorofluorescein Dibromofluorescein Br H H Na Na
534 Solvent Red 72 H Br H H H 490 Diiodofluorescein I H H Na Na 628
Eosin B NO.sub.2 Br H Na Na 624 Eosin Y Br Br H Na Na 692 Ethyl
Eosin Br Br H C.sub.2H.sub.5 K 714 Erythrosin B I I H Na Na 880
Phloxine B Br Br Cl Na Na 830 Rose Bengal I I Cl Na Na 1018
4,5,6,7-Tetrabromoerythrosin I I Br Na Na 1195
* * * * *