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 1 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 2 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 factors that 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 2 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 2 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.
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