EXCEED THE SPACE PROVIDED. There is a growing expectation that targeted drug delivery will greatly improve anticancer therapy. To accelerate attaining this goal, we introduced a new synthesis to prepare modular, biodegradable polyester dendritic polymers of various architectures. We showed that a Bow-tie architecture, with PEG on one dendron and doxorubicin on the other dendron, was a superior drug carrier in a murine tumor model. We will attach other drugs to the Bow-tie and test the hypothesis that optimal drug release rates are required for therapeutic success. We will also employ recent synthetic advances to devise novel dendritic polymers that: a.) Simultaneously deliver two drugs; b.) Have greater payloads and a targeting ligand; c.) Have improved linkages for drug attachment and controlled drug release. Using these novel macromolecules, we will test the following hypotheses related to the factorsthat contribute to superior anti-cancer therapy of the polymeric drug.
In specific aim 1, using the bow-tie polymers, we will test the hypothesis that a specified combination of polymer-drug uptake in the tumor and drug release rate from the polymer is required to optimize anti-tumor activity. We hypothesize that the optimal release rate will differ for each anticancer agent tested: doxorubicin, cis-platinum, a camptothecin derivative, a fluoropyrimidine and paclitaxel.
In specific aim 2, we will devise synthetic routes for attaching two of the above drugs, at defined ratios, to a single polymer. We will use this 'double barrel' polymer to test the hypothesis that the simultaneous delivery to rodent solid tumors of two appropriately selected drugs is synergistic compared to the drugs administered together but on different polymers or together as free drugs.
In specific aim 3, we will develop a new synthesis of polyester dendronized polymers of high molecular weight and with various architectures. We will examine the influence of molecular weight/architecture on the pharmacokinetic properties and targeting potential. We use the more promising polymer architectures to test the hypothesis that a high number of drugs per targeting ligand are required for effective ligand-mediated drug targeting. Completion of this research will enable, a variety of substantially improved targeted therapies and diagnostic imaging applications that can be successfully applied to treat humans with cancer. PERFORMANCE SITE ========================================Section End===========================================
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