Cross-linked Polymer Micelles in Cancer Therapy

描述（由申请人提供）：该项目的目标是开发一种最佳的顺铂抗肿瘤递送系统。这将通过使用交联纳米级聚合物胶束来实现。这些胶束的纳米制造涉及到二价金属阳离子将聚环氧乙烷（PEO）和聚羧酸的二嵌段共聚物缩聚成核壳形态的球形胶束。胶束的核心被化学交联，阳离子通过透析去除。核的离子特性允许顺铂的包封，而核的交联将抑制稀释时胶束的解离。因此，顺铂将避免过早释放。这样的结构将最大限度地提高临床效益，同时限制不良的副作用。事实上，装载顺铂的聚合物胶束将在体内长期循环，并提供顺铂的现场递送，由于增强的渗透性和滞留作用，胶束在肿瘤部位积累。顺铂进入细胞后，胶束将分解，这将使用具有二硫键的交联剂来实现，已知二硫键在细胞内环境中分裂。聚合物胶束的诱导降解将导致共聚物链的释放，这些共聚物链将通过肾脏清除而被清除。我们假设这些胶束可以作为顺铂全身递送的载体，以提高药物在癌症治疗中的疗效。综上所述，该提案解决了以下具体目标：(1)开发和表征具有交联离子核的聚合物胶束，可以有效地封装和释放顺铂；(2)确定顺铂掺入聚合物胶束是否增强了药物的细胞毒性作用；(3)利用体内肿瘤模型来确定顺铂掺入交联聚合物胶束是否会促进肿瘤消退。预计这些研究将导致顺铂新配方的设计，以改善癌症治疗。

DESCRIPTION (provided by applicant): 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.