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）：此II期STTR项目的目的是开发一种聚合系统，用于结合两种抗肿瘤剂，吉西他滨和紫杉醇。基于STTR I期奖的成功结果，该II期提案详细介绍了对两种新型的大分子分子治疗剂的综合和评估的基本原理和研究计划，这些疗效具有多种多样的互补作用方式，用于治疗卵巢癌。它们的设计基于新的，创新的长循环骨架降解的N-（2-羟丙基）甲基丙烯酰胺（HPMA）共聚物 - 药物共轭物。聚合物载体将由交替的HPMA共聚物段（块）和酶促降解的寡肽序列组成。每个构造将包含多个吉西他滨或紫杉醇的副本。这些药物通过溶酶体可降解的垫片附着在骨架上，该垫片将允许细胞内释放和生物活性。毒品的选择非常适合该项目的成功。吉西他滨是胞苷的合成核苷类似物。它的三磷酸代谢物被掺入DNA中，从而阻止细胞分裂。吉西他滨在几种卵巢癌模型中表现出活性，并已获得FDA批准用于卵巢癌的联合疗法。紫杉醇是一种有丝分裂抑制剂，通过稳定微管的作用，从而抑制其在细胞分裂期间的分解，目前被认为是第一线和随后治疗卵巢癌晚期阶段的治疗。由于EPR（增强的渗透性和保留）效应，新的，创新的骨干降解载体的漫长循环时间将导致肿瘤的积累增加。此外，两种聚合物 - 药物结合物与各种作用机制的结合将导致卵巢癌治疗的功效增强和最小的不良反应。该提案的具体目的是三个方面：a）缩放合成并表征可降解的可降解的HPMA共聚物毒剂（吉西他滨和紫杉醇）结合物，这些结合物包含含有酶促降解序列的骨干和侧链中的酶促降解序列； b）建立最大耐受剂量（MTD）以及结合物的急性毒性及其在体内的组合； c）评估体内缀合物的生物分布，清除率，抗癌功效和剂量升级研究。该项目的最终目的是将有效且可销售的药物结合与一种新型药物输送系统进行治疗，以治疗卵巢癌，其中这些药物位于肿瘤部位，化学疗法的不良反应被最小化并最大程度地提高了功效。