The objective of this project is to develop an optimal anti-tumor delivery system for cisplatin. This will be realized by utilizing cross-linked nanoscale size polymer micelles. The nanofabrication of these micelles involves condensation of diblock copolymers of poly(ethylene oxide) (PEO) and poly(carboxylic acid) by divalent metal cations into spherical micelles of core-shell morphology. The core of the micelles is then chemically cross-linked and cations removed by dialysis. The ionic character of the core allows for the encapsulation of cisplatin while the cross-linking of the core will suppress dissociation of the micelle upon dilution. As a result, cisplatin will be protected from premature release. Such a formation would maximize clinical benefit while limiting untoward side effects. Indeed, the cisplatin-loaded polymer micelles will be long circulating in the body and provide for on-site delivery of cisplatin with accumulation of the micelles at the tumor site due to enhanced permeability and retention effect. After delivery of cisplatin into the cells the micelles will disintegrate, which will be achieved using cross-linked agents with disulfide bonds that are known to cleave in the reducing intracellular environment. The induced degradation of the polymer micelle will result in the release of the copolymer chains that will be removed through renal clearance. We hypothesize that these micelles can be used as carriers for systemic delivery of cisplatin to improve drug efficacy in cancer treatment. Taken together, the proposal addresses the following specific aims: (1) development and characterization of polymer micelles with cross-linked ionic cores that can efficiently encapsulate and release cisplatin; (2) the determination of whether the incorporation of cisplatin into the polymer micelles potentiates cytotoxic effects of the drug; and (3) the utilization in vivo tumor models to determine whether incorporation of cisplatin into cross-linked polymer micelles enhances tumor regression. It is anticipated that these studies will lead to the design of new formulation of cisplatin for improved cancer treatment. ? ? ? ?
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