During the last three years we have successfully synthesized various hydrotropic polymers, hydrogels, dendrimers, and polymeric micelles that achieve solubility enhancement by several orders of magnitude for paclitaxel, a notoriously poorly soluble anticancer drug. The preliminary in vivo data using hydrotropic polymeric micelles have indicated that the therapeutically effective blood concentration of paclitaxel can be achieved if all of the loaded paclitaxel can be released during the GI transit time. The goal of this project is to synthesize hydrotropic polymer micelles that produce highly stable aqueous formulations but at the same time release paclitaxel fast upon contact with gastric and intestinal fluids. The hypothesis to be tested in this project is that the water-solubility of paclitaxel by 2-4 orders of magnitude overcomes the adverse effect of P-glycoprotein (Pgp) to result in clinically significant bioavailability.
The specific aims are: (1) to synthesize hydrotropic polymer micelles with various affinities to paclitaxel for controlling the paclitaxel release kinetics and mucoadhesive or inverse thermo-sensitive micelles for enhancing the GI transit time; (2) to control the in vitro paclitaxel release kinetics from the oral formulations; (3) to evaluate the cytotoxic efficacy of the formulations using human tumor cell lines; and (4) to examine the in vivo bioavailability using an in vivo chronically catheterized rat model. Since the increased bioavailability is based on the faster release of paclitaxel in the GI tract, the potential GI toxicity of the paclitaxel formulations will be examined by testing gastrointestinal permeability and by histological examination of the intestinal tissues. The fast release of paclitaxel will be achieved by introducing pH- sensitive moiety into the hydrotropic block so that the affinity to paclitaxel can be lowered by simple pH changes. This project is expected to produce novel hydrotropic polymeric micelle systems that have high drug loading efficiency, high stability, and yet fast release of the loaded paclitaxel in the GI tract. This will provide a new avenue of paclitaxel delivery by oral administration. The oral paclitaxel formulations are expected to have great therapeutic potential not only for cancer treatment as well as neurodegenerative diseases that can be potentially treated by paclitaxel. ? ?
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