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

描述(由申请人提供)：这项第一阶段提案详细说明了合成和表征靶向、主干可降解、长循环的聚合物结合物的原理和研究计划，每个大分子包含两种抗癌药物。聚合物载体将由交替的N-(2-羟丙基)甲基丙烯酰胺(HPMA)共聚物链段(块)和可酶降解的寡肽序列组成。每个结构将包含两种抗癌药物(紫杉醇和吉西他滨)和OV-TL16抗体(与大多数人卵巢癌表达的OA-3抗原互补)的Fab‘片段的多个副本。FDA批准的抗癌药物紫杉醇和吉西他滨的联合应用是临床评价的新组合之一。将这两种药物连接到Fab‘片段靶向、长循环(高分子量)主干可降解的HPMA共聚物载体上，将增强这两种药物向癌细胞的同时输送。由于Fab‘片段的生物识别而产生的主动靶向和由于EPR(增强渗透性和滞留)效应而产生的被动靶向的结合，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：a)设计、合成和表征Fab‘片段靶向的HPMA共聚物-紫杉醇/吉西他滨连接物；根据生物评价的反馈优化结构。B)体外评价这些结合物对人卵巢癌细胞的作用：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)聚合物药物结合物对裸鼠人卵巢癌异种移植模型的治疗效果。在完成第一阶段研究后，TheraTarget将确定合成和表征HPMA共聚药物结合物的可行性，评估它们的体外和体内活性，并选择领先的结合物进行第二阶段评估。该项目的最终目标是开发一种有效的、有市场价值的聚合物药物输送系统，能够显著提高卵巢癌患者的生存时间。 与公共健康相关：这项第一阶段提案详细说明了合成和表征每个大分子含有两种抗癌药物的主干可降解、长循环聚合物结合物的基本原理和研究计划。同时向卵巢癌细胞输送两种药物将导致疗效增强和不良反应最小，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.