Drug – bio-affecting and body treating compositions – Solid synthetic organic polymer as designated organic active... – Aftertreated polymer
Patent
1994-12-05
1998-06-09
Page, Thurman K.
Drug, bio-affecting and body treating compositions
Solid synthetic organic polymer as designated organic active...
Aftertreated polymer
424 7818, 424 7819, 424 7822, 424422, 424423, 424426, 424451, 424 7827, A61K 31765, A61K 31785, A61K 3180
Patent
active
057629188
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention provides novel conjugates for use in targeting a selected agent, and particularly, a steroid, to vascular endothelial cells. These conjugates comprise two components preferably linked by a selectively-hydrolyzable bond, such as an acid-labile bond. Firstly, a polyanionic compound such as a polyanionic polymer, which directs the conjugate to vascular endothelial cells, and secondly, a selected agent, such as a steroid, which exerts its action following cellular release. The invention provides novel conjugates that function as targeted angiogenesis inhibitors that are proposed for use in the treatment of pathological conditions such as cancer, arthritis, and diabetic blindness. Preferred inhibitors are those in which the polyanionic compound is a polysulfated polymer such as a heparin derivative, conjugated to a steroid with anti-angiogenic activity, such as cortisol, or derivatives and variants thereof.
DESCRIPTION OF THE RELATED ART
The control of endothelial cell proliferation is a vital part of normal homeostatic mechanisms. A disturbance in this process can result in, for example, excessive or inappropriate endothelial cell proliferation or activation which is often associated with disease processes. For example, the proliferation of vascular endothelial cells is vital to angiogenesis, the formation of new blood vessels, which in turn, is associated with many disabling or life-threatening disorders. These include cancer (Algire et al., 1945; Tannock, 1968; Folkman, 1972) and other pathological conditions such as diabetic retinopathy, atherosclerosis, rheumatoid arthritis, synovitis, psoriasis, dermatitis, endometriosis, encephalitis and tonsillitis (Brown & Weiss, 1988, Waltman et al., 1978; Gartner & Henkind, 1978; Moses & Langer, 1991). It is known that angiogenesis rarely occurs in healthy adult humans except during wound healing and during phases of the female reproductive cycle (Hobson & Denekamp, 1984).
In solid tumors, vascular endothelial cells divide about 35 times more rapidly than those in normal tissues, except the uterine epithelium (Denenkamp & Hobson, 1982). Such inappropriate proliferation is necessary for tumor growth and metastasis (Folkman, 1986). Vascular endothelial cell growth and division is also important in chronic inflammatory diseases such as rheumatoid arthritis, psoriasis and synovitis, where these cells proliferate in response to growth factors released within the inflammatory site (Brown & Weiss, 1988). In atherosclerosis, formation of the atherosclerotic plaque is triggered by a monoclonal expansion of endothelial cells in blood vessels (Alpern-Elran et al., 1989). Furthermore, in diabetic retinopathy, blindness is thought to be caused by basement membrane changes in the eye, which stimulate uncontrolled angiogenesis and consumption of the retina (West & Kumar, 1988).
Endothelial cells are also involved in graft rejection. In allograft rejection episodes, endothelial cells express proadhesive determinants that direct leukocyte traffic to the site of the graft. It is believed that the induction of leukocyte adhesion molecules on the endothelial cells in the graft may be induced by locally-released cytokines, as is known to occur in an inflammatory lesion.
As endothelial cells are involved in a wide variety of processes, it has been reasoned that drugs targeted to such cells may be of wide-ranging use clinically. Perhaps most importantly, angiogenesis inhibitors could potentially be of use in the treatment of those diseases, mentioned above, whose pathogenesis is influenced or maintained by the proliferation of vascular endothelial cells. Angiogenesis inhibitors would be particularly advantageous in the treatment of cancer, in which one of the current major problems is the emergence of drug-resistant malignant cells.
Within the last decade, several inhibitors of angiogenesis have been identified (Langer et al., 1976; Taylor & Folkman, 1982; Sharpe et al., 1990, Good et al., 1990, Ingber et al., 1990). For example, anti-angiog
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Bernstein
Board of Regents , The University of Texas System
Page Thurman K.
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