Drug – bio-affecting and body treating compositions – Radionuclide or intended radionuclide containing; adjuvant... – Molecular bilayer structure
Reexamination Certificate
1999-03-29
2001-08-14
Hartley, Michael G. (Department: 1619)
Drug, bio-affecting and body treating compositions
Radionuclide or intended radionuclide containing; adjuvant...
Molecular bilayer structure
C424S450000
Reexamination Certificate
active
06274116
ABSTRACT:
FIELD OF THE INVENTION
This invention generally relates to compositions and methods for treating tumors, and more particularly to compositions and methods for treating tumors using borane derivatives both free and liposome encapsulated.
BACKGROUND OF THE INVENTION
Neutron capture therapy is an attractive method for cancer therapy, specifically the treatment of malignant tumors. The generalized reaction involves capture of a thermalized neutron (usually from a nuclear reactor with special moderators and ports) by an appropriate nucleus having a large neutron capture cross-section. The subsequent decay emits energetic particles (alpha particles) which can kill nearby tumor cells. Since the energetic and cytotoxic alpha particles travel only about one cell diameter in tissue, preferably one may specify the cell type to be destroyed by placing the alpha particle precursors only on or within the tumor cells.
Boron-10 (also designated as
10
B), for example, has such an appropriate nucleus and has particularly advantageous properties for this scheme. The boron-10/thermal neutron capture reaction is as follows (* indicating an unstable intermediate state of the boron nucleus):
10
B+
1
n→[
11
B]*→
7
Li (0.87 Mev.)+
4
He (1.52 Mev.)
In order for this therapy to be effective, sufficient
10
B must be localized in a tumor to generate the required density of particles. This level has been variously estimated to be approximately 10-50 &mgr;g
10
B/gm tumor. Furthermore, the concentration of
10
B in normal tissue and blood should be limited and preferably less than the concentration in the tumor in order to minimize damage to healthy cells and blood vessels. H. Hatanaka (1986) Boron-Neutron Capture Therapy for Tumors; Nishimura Co., Ltd. p. 1-16.
Large numbers of boron containing compounds have been tested for their ability to satisfy the above criteria. With few exceptions, all have failed as not enough boron has localized in the tumor and the concentration in the blood has been too high for effective neutron capture therapy. Human clinical trials with Na
2
B
12
H
11
SH in Japan have shown some promise, but only for a limited group of brain tumors. Id. 16-26.
Neutron capture therapy would be greatly expanded in usefulness if a generalized method for delivering high concentrations of
10
B to tumors were available. It would further be useful if more
10
B collected in tumor than in the blood.
Recently it has become possible to deliver drugs and other compounds selectively to tumors using liposomes of a particular composition structure. See European Patent Application No. 87311040.7 published Jun. 22, 1988; U.S. Pat. No. 5,019,369 to Presant; and “Liposomes from Biophysics to Therapeutics”, M. J. Ostro, Ed., Marcel Dekker, Inc., New York (1987), all of which are incorporated herein by reference.
Incorporation of compounds with higher osmolarity inside the internal space of liposomes than outside, as is necessary for effective neutron capture therapy, depends on incorporating the highest concentration of
10
B possible without substantially altering the liposome's favorable biodistribution characteristics. Thus, the objective of at least 10 &mgr;g
10
B per gram of tumor tissue can be met (assuming use of greater than 90%
10
B enriched material).
Na
2
B
20
H
18
and its hydroxide derivatives are known. See M. F. Hawthorne, R. L. Pilling, and P. M. Garrett,
J. Am. Chem. Soc
. 87, 4740 (1965). It is known to use boron containing polyphosphonates for the treatment of calcific tumors. See European Patent Application No. 82200784.5 published May 1, 1983. Boronated porphyrin compounds for use in neutron capture therapy are also known. See U.S. Pat. No. 4,959,356 to Miura, U.S. Pat. No. 5,116,980 to Gabel and U.S. Pat. No. 4,466,952 to Hadd.
There is a continuing long felt but unmet need for a method of selectively delivering therapeutic concentrations of
10
B to tumors. There is a similar need for
10
B compositions and delivery vehicles which can be used in boron neutron capture therapy.
OBJECT OF THE INVENTION
It is an object of the invention to provide compositions and methods for delivering therapeutically useful concentrations of boron containing compounds to tumors for use in neutron capture tumor therapy.
It is a further object to provide borane and liposome encapsulated borane compounds that have the properties of retaining concentrations of said borane compounds inside the liposomes without significant breakage of the liposomes.
It is a further object of the invention to provide a method of cancer therapy through use of both free and liposomal encapsulated borane compounds with the means to deliver at least 10 micrograms
10
B per gram of tumor tissue to animal and human tumors, while minimizing the concentration of
10
B in the blood.
SUMMARY OF THE PREFERRED EMBODIMENTS
The above objectives are fulfilled by the present invention. In one aspect of the present invention therapeutically effective borane derivatives having two electron donors on the borane cage are encapsulated within the internal aqueous space of liposomes, and the liposomes thereafter administered to a tumor bearing patient. In another aspect of the present invention, certain free boranes useful for neutron capture therapy have been found to have favorable biodistributions. Preferably both free and liposome encapsulated Na
3
B
20
H
17
NH
3
are used in these aspects of the invention. In another aspect of the present invention, therapeutically effective carborane derivatives are embedded within the liposome bilayer for subsequent administration. The resulting liposomes have heightened tumor selectivity and can be used as an encapsulation vehicle for the previously mentioned borane derivatives and for other drugs. In yet another aspect of the present invention novel derivatized boranes are developed for use in boron neutron capture therapy.
REFERENCES:
patent: 5272250 (1993-12-01), Spielvogel et al.
patent: 5328678 (1994-07-01), Fujii et al.
patent: 5856551 (1999-01-01), Kane et al.
patent: 92/22298 (1992-12-01), None
Shelly K. et al., Model studies directed toward the boron neutron-capture therapy of cancer, Proc. Natl. Acad. Sci., vol. 89, pp. 9039-9043, Oct. 1992.
Feaks Debra Arlene
Hawthorne M. Frederick
Shelly Kenneth John
Hartley Michael G.
Koppel & Jacobs
Ram Michael J.
Reagents of the University of California
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