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: 8921139
• 负责人: JINDRICH H. KOPECEK
• 金额: $ 49.24万
• 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 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8921139
• 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; Health; 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; 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）：该二期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 I期奖项的成功结果，本II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治疗卵巢癌的合成和体内疗效评估的基本原理和研究计划。他们的设计是基于新的，创新的长循环骨架可降解的N-（2-羟丙基）甲基丙烯酰胺（HPMA）共聚物-药物偶联物。聚合物载体将由交替的HPMA共聚物片段（嵌段）和酶降解的寡肽序列组成。每个构建体将包含吉西他滨或紫杉醇的多个副本。药物通过溶酶体可降解的间隔物附着在骨架上，这将允许细胞内释放和生物活性。药物的选择对该项目的成功是个好兆头。吉西他滨是胞苷的合成核苷类似物。它的三磷酸代谢物与DNA结合，从而阻止细胞分裂。吉西他滨已在几种卵巢癌模型中显示出活性，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，其作用是稳定微管，从而抑制其在细胞分裂过程中的分解，目前被用于晚期卵巢癌的一线和后续治疗。新的、创新的骨干可降解载体的长循环时间将由于EPR（增强渗透性和滞留性）效应而导致肿瘤积累增加。此外，两种不同作用机制的高分子药物偶联物联合使用，可提高卵巢癌治疗的疗效，并将不良反应降至最低。该提案的具体目标有三个方面：a)扩大合成规模并表征在主链和侧链中含有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）偶联物；b)确定最大耐受剂量（MTD）以及缀合物及其组合在体内的急性毒性；c)评估结合物在体内的生物分布、清除、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的、可销售的药物组合和一种新的药物输送系统，用于治疗卵巢癌，其中药物定位在肿瘤部位，化疗的不良反应最小化，疗效最大化。