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

描述（由申请人提供）：该I期提案详细说明了合成和表征靶向、骨干可降解、长循环聚合物偶联物的基本原理和研究计划，每个大分子含有两种抗癌药物。聚合物载体将由交替的N-（2-羟丙基）甲基丙烯酰胺（HPMA）共聚物片段（嵌段）和酶降解的寡肽序列组成。每个构建体将包含两种抗癌药物（紫杉醇和吉西他滨）和OV-TL16抗体Fab'片段的多个拷贝（与大多数人类卵巢癌上表达的OA-3抗原互补）。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组合之一。将两种药物附着在Fab的靶向片段、长循环（高分子量）可降解的HPMA共聚物载体上，将增强两种药物同时递送到癌细胞。由于Fab'片段的生物识别，主动靶向与由于EPR（增强渗透性和滞留性）效应的被动靶向相结合，将导致增强的疗效和最小的不良反应，从而提高癌症治疗的有效性。该提案的具体目标有三个方面：A) Fab'片段靶向HPMA共聚物-紫杉醇/吉西他滨偶联物的设计、合成和表征；基于生物评价反馈的结构优化。B)体外对人卵巢癌细胞偶联物的评价：内化和亚细胞命运，稳定性和酶催化药物释放，以及细胞毒性。C)聚合物-药物偶联物对裸鼠人卵巢癌异种移植瘤模型的治疗效果。通过I期研究的完成，TheraTarget将建立合成和表征HPMA共聚物-药物偶联物的可行性，评估其体外和体内活性，并选择主要的偶联物进行II期评估。该项目的最终目标是开发一种有效的、可销售的聚合物给药系统，能够显著提高卵巢癌患者的生存时间。

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.