Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
1999-07-13
2001-12-18
Fonda, Kathleen Kahler (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S410000, C536S103000
Reexamination Certificate
active
06331530
ABSTRACT:
BACKGROUND OF THE INVENTION
Throughout this application, various publications are referenced in parentheses by author and year. Full citations for these references may be found at the end of the specification immediately preceding the claims. The disclosures of these publications in their entireties are hereby incorporated by reference into this application to more fully describe the state of the art to which this invention pertains.
Photodynamic therapy of cancers uses a combination of light-activated drugs (photosensitizers) and laser light to create highly reactive forms of oxygen (singlet oxygen) that destroy tumor cells. Porphyrinoid dyes are photosensitizers which are widely used in photodynamic therapy. However, one major drawback of these hydrophobic photosensitizers is that they are not selective to tumor tissue because they are transported to every organ by blood lipoproteins of the blood stream (Moser et al., 1994). One way to prevent this is to attach the photosensitizer to cancer-specific antibodies and use cyclodextrin dimers to encapsulate the dye so that it cannot interact with lipoproteins (Ruebner et al., 1996, 1997).
Another strategy is presented in the present application, which contains the first disclosure of &bgr;-cyclodextrin dimers having a cleavable linker between two &bgr;-cyclodextrin molecules. The &bgr;-cyclodextrin dimers can serve as hydrophilic carriers for photosensitizers, which can be administered to a subject with cancer. The &bgr;-cyclodextrin dimer can be cleaved by light, which can be selectively directed at the tumor site. The dye will then be released and be able to go into tumor cells. After the dimer is cleaved, the concentration of uncleaved &bgr;-cyclodextrin dimers at the tumor site will be reduced and more uncleaved &bgr;-cyclodextrin dimers will diffuse into the tumor site due to the concentration gradient. In this way, photosensitizer can be concentrated in the tumor without the use of a cancer-specific antibody.
SUMMARY OF THE INVENTION
The invention provides a composition of matter comprising two &bgr;-cyclodextrin molecules and a cleavable linker attached to and joining each such &bgr;-cyclodextrin.
This invention further provides a composition which comprises a hydrophilic matrix comprising the above-described composition of matter and a photosensitizer encapsulated within the matrix, wherein the cleavable linker is cleaved upon exposure to light of a wavelength appropriate for the light to be absorbed by the photosensitizer.
This invention also provides a method of killing a tumor cell which comprises bringing into proximity with the tumor cell the above-described composition and exposing the composition to light so as to cleave the cleavable linker and release the photosensitizer.
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Breslow, R., Halfon, S., and Zhang, B. (1995) Molecular recognition by cyclodextrin dimers. Tetrahedron 51: 377-388.
Moser, J.G., Heuermann, A., Oehr, P., Scheer, H., Vervoots, A., and Andrees, S. (1994) Carrier systems in PDT: On the way to novel anti-tumor drugs. SIPE Conf. Proc. vol. 2325 Photodynamic Therapy of Cancer II, pp 92-99.
Moser, J.G., Ruebner, A., Vervoots, A., and Wagner, B. (1996) Cyclodextrin dimers used to prevent side effects of photochemotherapy and general tumor chemotherapy. In: Szejtli, J. and Szente, L. (eds.), Proceedings of the Eight International Symposium on Cyclodextrons, Kluwer Academic Publishers, pp 71-76.
Ruebner, A. et al. (1996) Synthesis of &bgr;-cyclodextrin dimers as carrier systems for photodynamic therapy of cancer. In: Szejtli, J. and Szente, L. (eds.), Proceedings of the Eight International Symposium on Cyclodextrons, Kluwer Academic Publishers, pp 77-80.
Ruebner, A. et al. (1997) Dimeric cyclodextrin carriers with high binding affinity to porphyrinoid photosensitizers. Journal of Inclusion Phenomena and Molecular Recognition in Chemistry 27: 69-84.
Sauter, M. and Adam, W. (1995) Oxyfunctionalization of benzofurans by singlet oxygen, dioxiranes, and peracids: chemical model studies for the DNA-damaging activity of benzofuran dioxetanes (oxidation) and epoxides (alkylation). Acc. Chem. Res. 28: 289-298.
Breslow Ronald
Ruebner Anja
Yang Zhiwei
Cooper & Dunham LLP
Fonda Kathleen Kahler
The Trustees of Columbia University in the City of New York
White John P.
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