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An intratumoral controlled release formulation of clusterin antisense oligonucleotide and paclitaxel or docetaxel for treatment of prostate tumors Springate, Christopher Michael Kevin

Abstract

Surgical procedures performed on blood vessels may cause irritation of the vessel wall. This irritation sets off a series of complicated steps, which results in a growth of the vessel wall towards the center of the blood vessel, and a narrowing of the amount of space for the blood to flow through. This process is called restenosis. Restenosis of the treated artery is a major complication of percutaneous transluminal coronary angioplasty (PTCA) and coronary artery bypass grafting. This intimal hyperplasia (thickening of the intimal layer of the blood vessel) is due to the differentiation, migration, and proliferation of connective tissue and vascular smooth muscle cells at the site of vascular injury (Mishaly, 1997). Through this process the arterial lumen may be enclosed by the neointima and thus compromise coronary blood flow. Paclitaxel stabilizes microtubules and in this way inhibits differentiation of vascular smooth muscle cells from a contractile phenotype to a migratory and proliferative phenotype in vitro. In vivo paclitaxel has inhibited vascular smooth muscle cell migration and proliferation in rabbits and in the rat carotid artery model. Drug delivery to the adventitia of the blood vessel may target events occurring in the adventitia, media, and intima. Perivascular drug delivery devices have delivered drugs that reduce stenosis in arteries in animal models. The objective of this work was to develop a flexible, biocompatible, paclitaxel loaded polymer film for perivascular application, to provide controlled release of paclitaxel over several weeks. Poly(ethylene-co-vinyl acetate) (EVA) with monomer ratios of 60/40 and 72/28, and polyurethane, were cast into films with various loadings of paclitaxel. These polymers were chosen because of their biocompatibility, hydrophobicity, flexibility, and because they are nondegradable. Perivascular films were manufactured from 60/40 EVA, 72/28 EVA or polyurethane, with various loadings of paclitaxel and sterilized by yirradiation. The physicochemical properties, and diffusion and release characteristics of paclitaxel in these films were investigated in this work. Paclitaxel existed within the EVA matrices as a granular, amorphous solid, whereas paclitaxel was miscible with the polyurethane matrices, y-irradiation of paclitaxel loaded EVA films resulted in cross-linking of the polymer chains, whereas yirradiation of polyurethane films resulted in polymer chain scission. Partitioning, permeability, and diffusion coefficients of paclitaxel in EVA and polyurethane were determined, and were similar for the two different types of matrices. Paclitaxel release from EVA and polyurethane films was linear with the square root of time, and with the square root of the loading concentration, for the first several days. Paclitaxel release from EVA and polyurethane films was by diffusion without the creation of channels or pores, and followed the Higuchi model of release for the first several days. Paclitaxel release from 60/40 EVA, 72/28 EVA, and polyurethane, was influenced by polymer monomer ratio, polymer type, and drug loading. Given the effects of sterilization on paclitaxel loaded 60/40 EVA, 72/28 EVA, and polyurethane films, polyurethane films showed the most promising potential for developing a film for the controlled release of paclitaxel for perivascular application for the inhibition of restenosis.

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