Backbone Degradable Polymer-drug Conjugates for the Treatment of Ovarian Cancer

描述（由申请方提供）：本I期提案详细描述了每个大分子含有两种抗癌药物的靶向、主链可降解、长循环聚合物偶联物的合成和表征的原理和研究计划。聚合物载体将由交替的N-（2-羟丙基）甲基丙烯酰胺（HPMA）共聚物链段（嵌段）和酶可降解的寡肽序列组成。每个构建体将含有两种抗癌药物（紫杉醇和吉西他滨）和OV-TL 16抗体的Fab'片段（与大多数人卵巢癌上表达的OA-3抗原互补）的多个拷贝。美国FDA批准的抗癌药物紫杉醇和吉西他滨的组合是临床评估的新型组合之一。两种药物与Fab'片段靶向的长循环（高分子量）主链可降解HPMA共聚物载体的连接将导致两种药物向癌细胞的增强和同时递送。由于Fab'片段的生物识别，主动靶向和由于EPR（增强的渗透性和保留）效应，被动靶向的组合将导致增强的功效和最小的副作用，从而改善癌症治疗的有用性。A）Fab'片段靶向HPMA共聚物-紫杉醇/吉西他滨缀合物的设计、合成和表征;基于来自生物学评价的反馈优化结构。B）缀合物对人卵巢癌细胞的体外评价：内化和亚细胞命运、稳定性和酶催化的药物释放以及细胞毒性。C）聚合物-药物缀合物对裸鼠中的人卵巢癌异种移植物模型的治疗功效。通过完成I期研究，TheraTarget将确定HPMA共聚物-药物缀合物的合成和表征的可行性，评估其体外和体内活性，并选择用于II期评估的主要缀合物。该项目的最终目标是开发一种有效且可销售的聚合物药物递送系统，能够显着提高卵巢癌患者的生存时间。 公共卫生相关性：该I期提案详细说明了每个大分子含有两种抗癌药物的主链可降解、长循环聚合物缀合物的合成和表征的基本原理和研究计划。同时向卵巢癌细胞递送两种药物将导致增强的疗效和最小的副作用，从而提高癌症治疗的有效性。

DESCRIPTION (provided by applicant): This Phase I proposal details the rationale and the research plan for the synthesis and characterization of targeted, backbone degradable, long-circulating polymer conjugates containing two anticancer drugs per macromolecule. The polymeric carrier will be composed of alternating N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer segments (blocks) and enzymatically degradable oligopeptide sequences. Each construct will contain multiple copies of two anticancer drugs (paclitaxel and gemcitabine) and of Fab' fragment of the OV-TL16 antibody (complementary to OA-3 antigen expressed on the majority of human ovarian carcinomas). The combination of FDA approved anticancer drugs, paclitaxel and gemcitabine, is one of novel combinations evaluated in the clinics. Attachment of both drugs to the Fab' fragment-targeted, long-circulating (high molecular weight) backbone degradable HPMA copolymer carrier will result in enhanced and simultaneous delivery of both drugs to cancer cells. The combination of active targeting, due to biorecognition of the Fab' fragments, and of passive targeting, due to the EPR (enhanced permeability and retention) effect, will result in augmented efficacy and minimal adverse effects, thus improving the usefulness of cancer therapy. The specific aims of the proposal are three-fold: A) Design, synthesis, and characterization of Fab' fragment- targeted HPMA copolymer-paclitaxel/gemcitabine conjugates; optimization of the structure based on feedback from biological evaluation. B) Evaluation of the conjugates on human ovarian cancer cells in vitro: internalization and subcellular fate, stability and enzymatically catalyzed drug release, and cytotoxicity. C) Therapeutic efficacy of polymer-drug conjugates on a human ovarian carcinoma xenograft model in nude mice. By completion of the Phase I studies TheraTarget will have established the feasibility of synthesis and characterization of the HPMA copolymer-drug conjugates, evaluated their activity in vitro and in vivo, and selected the leading conjugate for Phase II evaluation. The ultimate goal of the project is the development of an effective and marketable polymer drug delivery system capable of significantly improving the survival time of ovarian cancer patients. PUBLIC HEALTH RELEVANCE: This Phase I proposal details the rationale and the research plan for the synthesis and characterization of backbone degradable, long-circulating polymer conjugates containing two anticancer drugs per macromolecule. The simultaneous delivery of two drugs to ovarian cancer cells will result in enhanced efficacy and minimal adverse effects, thus improving the usefulness of cancer therapy.