We describe a new, robust and economical chemical approach to prepare modular biodegradable dendritic polymers with narrow polydispersities. These novel materials can potentially be used as polymeric drug carriers, in sustained drug delivery systems or to coat implantable bioengineered medical devices. We will test the hypothesis that dendritic polymeric drugs with the appropriate molecular weight, architecture, drug and bioreversible drug linkages, provide improved biodistribution properties that result in superior anti-cancer drug therapy compared to the parent drug.
In specific aim number 1 we will devise flexible synthetic methods for the preparation of biocompatible dendritic carriers. We developed a new, rapid and low cost synthesis of these dendritic molecules that eliminate the need for the tedious purification steps required for most dendrimers. We will develop additional synthetic methods and optimize molecular architecture, functionality, and modularity that will greatly extend the versatility of this promising class of multivalent drug carriers for targeted drug delivery.
In specific aim number 2, we will determine the effects of polymer mass and architecture on physico-chemical properties in solution and pharmacokinetic behavior in mice. The physical properties of these polymers will be determined using a combination of characterization techniques, including light scattering measurements, gel permeation chromatography, and STM. Subsequent in vitro and in vivo experiments will be conducted to determine the cellular uptake, pharmacokinetics, biodistribution and tumor uptake of attached materials in tumor-bearing mice.
In specific aim number 3 we will determine the potency of polymeric- anticancer drugs against a human breast cancer in a xenograft solid tumor murine model as function of polymer attributes, targeting ligand, drug type, drug loading and drug release mechanism. It is anticipated that dendritic polymers with appropriate MW and architecture will better exploit the enhanced penetration and retention phenomenon found in solid tumors; hence lead to improved anti-tumor therapy. Success in this research will greatly improve our ability to design polymeric drug carriers that would be extremely difficult to prepare using other methods of polymer synthesis and that enable the optimization of the pharmacokinetic properties for a wide variety of targeted therapeutic and imaging applications.
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