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: 8779604
• 负责人: JINDRICH H. KOPECEK
• 金额: $ 50.29万
• 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 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8779604
• 关键词: Acute; Adverse effects; Animal Model; Antimitotic Agents; Antineoplastic Agents; Award; Biocompatible; Biodistribution; Cancer Model; Cell division; Clinic; Clinical Trials; Collaborations; Combined Modality Therapy; Cytidine; DNA; Data; Development; Dose; Dose-Limiting; Drug Carriers; Drug Combinations; Drug Delivery Systems; Evaluation; FDA approved; Generations; Goals; Investigational Drugs; Laboratories; Legal patent; Malignant neoplasm of ovary; Maximum Tolerated Dose; Microtubules; Molecular Weight; Mus; Oligopeptides; Organ; Ovarian Carcinoma; Paclitaxel; Permeability; Pharmaceutical Preparations; Phase; Polymers; Publications; Regimen; Research; Resource Allocation; Side; Site; Small Business Technology Transfer Research; Staging; System; Therapeutic; Time; TimeLine; Toxic effect; Translations; Treatment Efficacy; Treatment Protocols; Treatment outcome; United States National Institutes of Health; Vertebral column; X-Ray Computed Tomography; base; biodegradable polymer; cancer therapy; chemical synthesis; chemotherapy; copolymer; design; gemcitabine; in vivo; innovation; methacrylamide; novel; nucleoside analog; ovarian neoplasm; preclinical study; protein aminoacid sequence; public health relevance; scale up; single photon emission computed tomography; success; tripolyphosphate; tumor

DESCRIPTION (provided by applicant): The purpose of this Phase II STTR project is to develop a polymeric system for the combination delivery of two antineoplastic agents, gemcitabine and paclitaxel. Based on the successful results of the STTR Phase I award, this Phase II proposal details the rationale and research plan for the synthesis and evaluation of in vivo efficacy of two novel macromolecular therapeutics with diverse and complementary mode of action for the treatment of ovarian carcinoma. Their design is based on new, innovative long-circulating backbone degradable N-(2- hydroxypropyl)methacrylamide (HPMA) copolymer - drug conjugates. The polymeric carrier will be composed of alternating HPMA copolymer segments (blocks) and enzymatically degradable oligopeptide sequences. Each construct will contain multiple copies of either gemcitabine or paclitaxel. The drugs are attached to the backbone via a lysosomally degradable spacer that will allow intracellular release and bioactivity. The choice of drugs bodes well for the success of the project. Gemcitabine is a synthetic nucleoside analog of cytidine. Its triphosphate metabolite is incorporated into DNA, thereby stopping cell division. Gemcitabine has demonstrated activity in several ovarian cancer models and has been approved by FDA for combination therapy of ovarian cancer. Paclitaxel is a mitotic inhibitor, which acts by stabilizing microtubules, thereby inhibiting their breakdown during cellular division It is currently indicated as first-line and subsequent therapy for the treatment of advanced stages of ovarian cancer. The long circulating time of the new, innovative backbone degradable carriers will result in augmented tumor accumulation due to the EPR (enhanced permeability and retention) effect. In addition, the combination of two polymer-drug conjugates with diverse mechanisms of action will result in enhanced efficacy of ovarian cancer treatment and minimal adverse effects. The specific aims of the proposal are three-fold: a) To scale up of the synthesis and to characterize backbone degradable HPMA copolymer-drug (gemcitabine and paclitaxel) conjugates containing enzymatically degradable sequences in the backbone and in side chains; b) To establish the maximum tolerated dose (MTD) as well as the acute toxicity of the conjugates and their combination in vivo; and c) To evaluate the biodistribution, clearance, anticancer efficacy and dose escalation studies of the conjugates in vivo. The ultimate goal of this project is to develop an effective and marketable drug combination with a novel drug delivery system for the treatment of ovarian cancer where the drugs are localized at the site of the tumor, adverse effects of chemotherapy are minimized and efficacy maximized.

描述（由申请人提供）：该第二阶段 STTR 项目的目的是开发一种用于联合递送两种抗肿瘤药物吉西他滨和紫杉醇的聚合物系统。基于 STTR 一期奖的成功结果，该二期提案详细介绍了两种具有不同和互补作用模式的新型大分子疗法治疗卵巢癌的体内疗效的合成和评估的基本原理和研究计划。他们的设计基于新型、创新的长循环主链可降解N-(2-羟丙基)甲基丙烯酰胺(HPMA)共聚物-药物缀合物。聚合物载体将由交替的 HPMA 共聚物片段（嵌段）和可酶促降解的寡肽序列组成。每个构建体将包含吉西他滨或紫杉醇的多个副本。这些药物通过溶酶体可降解的间隔物附着在主链上，从而允许细胞内释放和生物活性。药物的选择预示着该项目的成功。吉西他滨是胞苷的合成核苷类似物。其三磷酸代谢物被掺入DNA中，从而阻止细胞分裂。吉西他滨已在多种卵巢癌模型中表现出活性，并已被 FDA 批准用于卵巢癌的联合治疗。紫杉醇是一种有丝分裂抑制剂，通过稳定微管发挥作用，从而抑制细胞分裂过程中的分解。目前被认为是治疗晚期卵巢癌的一线和后续疗法。由于EPR（增强渗透性和保留）效应，新型创新骨干可降解载体的长循环时间将导致肿瘤积累增加。此外，两种具有不同作用机制的聚合物-药物缀合物的组合将增强卵巢癌治疗的功效并最小化副作用。该提案的具体目标有三个： a) 扩大合成规模并表征主链和侧链中含有可酶降解序列的主链可降解 HPMA 共聚物药物（吉西他滨和紫杉醇）缀合物； b) 确定缀合物及其组合的体内最大耐受剂量（MTD）以及急性毒性； c) 评估缀合物的体内生物分布、清除率、抗癌功效和剂量递增研究。该项目的最终目标是开发一种有效且可销售的药物组合，并采用新颖的药物输送系统来治疗卵巢癌，其中药物定位于肿瘤部位，最大限度地减少化疗的副作用并最大限度地提高疗效。