Innovative drug delivery platform based on biocompatible poly(2-oxazoline)s block copolymers is proposed to improve chemotherapy of cancer. The technology will overcome major therapeutic challenges in breast cancer. This will be realized by tailoring poly(2-oxazoline)s structure to incorporate very large amounts (>40 wt. %) of insoluble drugs in polymer micelles of narrow size distribution (20-50 nm). These high-capacity micelles can be lyophilized and re-dispersed without loss of the particle size, drug loading or drug activity. The micelles will carry paclitaxel and docetaxel using drastically less amount of excipients relative to current formulations. Hence, excipient-associated toxicities will be decreased. The micelles will be targeted using monoclonal antibodies to Her2-receptors. This strategy is expected to address Herceptin resistance in cancers overexpressing Her2. The proposed aims will 1) optimize poly(2-oxazoline)s structures for solubilization of water-insoluble drugs;2) determine pharmacokinetics and maximum tolerated doses in vivo;3) validate anti-tumor activity in mouse models of breast cancer, and 4) develop targeted micelles effective against Herceptin sensitive and resistant tumors. This CNPP joins together pharmaceutical scientists at [deleted], cancer researchers at [deleted], and polymer chemists at [deleted] who will contribute to the Alliance through challenge projects and other trans-alliance activities.
Overcoming the historical limitations of dose-limiting toxicities, life-threatening side effects, and low water solubility of potentially highly-active drug candidates could result in the development of effective drug delivery systems that provide safety, bioavailability, and ease of use.
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