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

用于治疗卵巢癌的主链可降解聚合物-药物缀合物

• 批准号: 8124344
• 负责人: Darwin Leroy Cheney
• 金额: $ 14.83万
• 依托单位: THERATARGET
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-26 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8124344
• 关键词: Adverse effects; Antibodies; Antigens; Antineoplastic Agents; Binding; Biological feedback; Cancer Patient; Clinic; Development; Drug Carriers; Drug Delivery Systems; Evaluation; FDA approved; Fab Immunoglobulins; Generations; Goals; Human; In Vitro; Malignant neoplasm of ovary; Molecular Weight; Nude Mice; Oligopeptides; Ovarian Carcinoma; Paclitaxel; Permeability; Pharmaceutical Preparations; Phase; Polymers; Reaction; Research; Small Business Technology Transfer Research; Structure; Testing; Therapeutic; Time; Treatment Efficacy; Vertebral column; Xenograft Model; Xenograft procedure; anti-cancer therapeutic; anticancer activity; base; biodegradable polymer; cancer cell; cancer therapy; copolymer; cytotoxicity; design; gemcitabine; improved; in vitro Assay; in vitro activity; in vivo; indexing; macromolecule; methacrylamide; mouse model; nanomedicine; novel; phase 1 study; polymerization; synergism; targeted delivery; tumor xenograft

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.

描述（由申请人提供）：该第一阶段提案详细介绍了每个大分子含有两种抗癌药物的靶向、主链可降解、长循环聚合物缀合物的合成和表征的基本原理和研究计划。聚合物载体将由交替的N-(2-羟丙基)甲基丙烯酰胺(HPMA)共聚物片段(嵌段)和可酶促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 抗体的 Fab' 片段（与大多数人类卵巢癌上表达的 OA-3 抗原互补）的多个副本。 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。将两种药物附着到 Fab' 片段靶向、长循环（高分子量）主链可降解 HPMA 共聚物载体上将导致两种药物同时向癌细胞的递送增强。由于 Fab' 片段的生物识别而产生的主动靶向与由于 EPR（增强渗透性和保留）效应而产生的被动靶向相结合，将提高疗效并最小化不良反应，从而提高癌症治疗的有效性。该提案的具体目标有三个： A) 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；基于生物学评价反馈的结构优化。 B) 缀合物对人卵巢癌细胞的体外评价：内化和亚细胞命运、稳定性和酶催化药物释放以及细胞毒性。 C)聚合物-药物缀合物对人卵巢癌裸鼠异种移植模型的治疗效果。通过完成第一阶段研究，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，并选择领先的缀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。 公共健康相关性：该第一阶段提案详细介绍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。同时向卵巢癌细胞输送两种药物将提高疗效并最小化副作用，从而提高癌症治疗的有效性。

项目成果

Indium-based and iodine-based labeling of HPMA copolymer-epirubicin conjugates: Impact of structure on the in vivo fate.

• DOI: 10.1016/j.jconrel.2016.06.004
• 发表时间: 2016-08-10
• 期刊: Journal of controlled release : official journal of the Controlled Release Society
• 作者: Zhang L;Zhang R;Yang J;Wang J;Kopeček J
• 通讯作者: Kopeček J

Synthesis and evaluation of a backbone biodegradable multiblock HPMA copolymer nanocarrier for the systemic delivery of paclitaxel.

• DOI: 10.1016/j.jconrel.2012.12.009
• 发表时间: 2013-02-28
• 期刊: Journal of controlled release : official journal of the Controlled Release Society
• 作者: Zhang R;Luo K;Yang J;Sima M;Sun Y;Janát-Amsbury MM;Kopeček J
• 通讯作者: Kopeček J

Biodegradable multiblock poly(N-2-hydroxypropyl)methacrylamide gemcitabine and paclitaxel conjugates for ovarian cancer cell combination treatment.

• DOI: 10.1016/j.ijpharm.2013.06.046
• 发表时间: 2013-09-15
• 期刊: INTERNATIONAL JOURNAL OF PHARMACEUTICS
• 影响因子: 5.8
• 作者: Larson, Nate;Yang, Jiyuan;Ray, Abhijit;Cheney, Darwin L.;Ghandehari, Hamidreza;Kopecek, Jindrich
• 通讯作者: Kopecek, Jindrich

FRET-trackable biodegradable HPMA copolymer-epirubicin conjugates for ovarian carcinoma therapy.

• DOI: 10.1016/j.jconrel.2015.09.045
• 发表时间: 2015-11-28
• 期刊: Journal of controlled release : official journal of the Controlled Release Society
• 作者: Yang J;Zhang R;Radford DC;Kopeček J
• 通讯作者: Kopeček J