The efforts proposed describe the thorough investigation of a class of dendrimers to determine whether these monodisperse, engineerable macromolecules are suitable vehicles for drug delivery. Their size suggests that the EPR effect can be exploited to target tumors. The ability to decorate these architectures with homing peptides allows for the investigation of """"""""magic bullet"""""""" stategies. The proposal focuses on Pt-coordination complexes, as the collaborator has great interest in this agent. The biological studies will be executed by the collaborator in conjunction with students from the PI's laboratory.This proposal addresses two specific aims:1) Can the dendrimers be targeted to tumors using passive and/or active strategies? The enhanced permeability and retention of polymers by tumors offers a passive mechanism for targeting these tissues for destruction. Attaching homing peptides to the polymeric drug delivery vehicle offers an additional active strategy to further discriminate the diseased tissue from host tissue. These experiments will be executed by looking at the biodistribution of labeled dendrimers that differ in size and composition. Strategies for screening compositions efficiently, and evaluating libraries of homing peptides are described.2) Can the dendrimers be loaded with cytotoxins and display suitable anticancer activity? Platinum will be loaded using dendrimers through pendant malonate groups. Release from the malonate is triggered in response to a change in pH. Other cytotoxins will be conjugated using reversible or biolabile linkages. The ability of these dendrimers to noncovalently sequester anticancer agents is also explored.
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