Cross-linked Polymer Micelles in Cancer Therapy

描述（由申请人提供）：本项目的目的是开发顺铂的最佳抗肿瘤递送系统。这将通过利用交联的纳米级尺寸的聚合物胶束来实现。这些胶束的纳米纤维化涉及聚（环氧乙烷）（PEO）和聚（羧酸）的二嵌段共聚物通过二价金属阳离子缩合成核-壳形态的球形胶束。然后胶束的核心被化学交联，阳离子通过透析被除去。核心的离子特性允许顺铂的包封，而核心的交联将抑制胶束在稀释时的解离。因此，顺铂将被保护免于过早释放。这样的形成将最大化临床益处，同时限制不利的副作用。事实上，负载顺铂的聚合物胶束将在体内长时间循环，并且由于增强的渗透性和保留效应，提供顺铂的原位递送，同时胶束在肿瘤部位累积。在将顺铂递送到细胞中之后，胶束将分解，这将使用具有已知在还原性细胞内环境中裂解的二硫键的交联剂来实现。聚合物胶束的诱导降解将导致共聚物链的释放，该共聚物链将通过肾清除率被去除。我们假设这些胶束可以用作顺铂全身递送的载体，以提高癌症治疗中的药物疗效。总之，该提案提出了以下具体目标：（1）开发和表征具有交联离子核的聚合物胶束，其可以有效地包封和释放顺铂;（2）确定将顺铂掺入聚合物胶束中是否增强药物的细胞毒性作用;和（3）利用体内肿瘤模型来确定将顺铂掺入交联聚合物胶束中是否增强肿瘤消退。预期这些研究将导致设计用于改善癌症治疗的顺铂的新制剂。

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.