Targeted Polymeric Combination Delivery for Treatment of Ovarian Cancer

用于治疗卵巢癌的靶向聚合物组合递送

• 批准号: 7999063
• 负责人: Hamid Ghandehari
• 金额: $ 10万
• 依托单位: THERATARGET
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7999063
• 关键词: Acute; Adverse effects; Angiogenesis Inhibitors; Antineoplastic Agents; Arginine; Aspartate; Binding; Biocompatible; Biological; Blood; Buffers; Calibration; Cancer Patient; Cancer cell line; Chronic; Combined Modality Therapy; Conduct Clinical Trials; Development; Dose; Drug Carriers; Drug Combinations; Drug Delivery Systems; Drug Evaluation; Ensure; Enzymes; Evaluation; FDA approved; Geldanamycin; Geldanamycin Analogue; Glycine; Goals; Human; In Vitro; Leucine; Ligands; Lysosomes; Malignant neoplasm of ovary; Methods; Microtubules; Molecular Weight; Peptides; Pharmaceutical Preparations; Phase; Phenylalanine; Physiological; Polymers; Preparation; Research; Series; Serum; Side; Site; Small Business Technology Transfer Research; Survival Rate; System; Time; Toxic effect; Vertebral column; Water; cancer cell; chemotherapy; copolymer; cytotoxicity; docetaxel; immunogenic; improved; in vivo; methacrylamide; novel; phase 2 study; preclinical study; public health relevance; receptor; tumor

DESCRIPTION (provided by applicant): This Phase I proposal details the rationale and the research plan for the synthesis and characterization of a polymeric delivery system that will deliver two anticancer drugs with diverse mechanisms of action simultaneously into ovarian cancer cells. The delivery system will be composed of N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer as the backbone. It is a well characterized, water-soluble, biocompatible, non-immunogenic and non-toxic synthetic polymeric drug carrier. Attached to the backbone will be a geldanamycin analog which has a well known dual mode of action (antiangiogenic and antitumor) and docetaxel, an FDA approved antineoplastic agent which acts by stabilizing microtubules. The drugs will be attached to the backbone via a lysosomally degradable spacer that will allow intracellular release and bioactivity; and (3) a cyclic tripeptide containing ligand that will target the HPMA conjugates to tumor-associated receptors. The novelty of this approach is that the geldanamycin analog and docetaxel, with their different mechanisms of action, will be attached to the same polymer backbone containing a targeting moiety, thereby ensuring the delivery of both the drugs simultaneously to the cancer cells. The aims are three fold: (1) synthesize and physiochemically characterize HPMA copolymers with the geldanamycin analog, docetaxel and the targeting tripeptide in the side chains; (2) characterize the stability and release profile of the HPMA conjugates; and (3) characterize the binding and cytotoxicity of the HPMA conjugates by biological methods in ovarian cancer cell lines. The ultimate goal of this project is the development of an effective and marketable drug combination with novel drug delivery systems 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. PUBLIC HEALTH RELEVANCE: This Phase I proposal details the rationale and the research plan for the synthesis and characterization of a polymeric delivery system that will deliver two anticancer drugs with diverse mechanisms of action simultaneously into ovarian cancer cells. This combination therapy will minimize the adverse effects of chemotherapy and maximize efficacy, thereby improving significantly the five year survival rate for ovarian cancer patients.

描述（由申请人提供）：本I阶段建议详细介绍了聚合输送系统的合成和表征的基本原理和研究计划，该系统将同时将具有不同作用机制的两种抗癌药物交付到卵巢癌细胞中。递送系统将由N-（2-羟基丙酰基）甲基丙烯酰胺（HPMA）共聚物作为骨架组成。这是一个特征性的，水溶性的，生物相容性的，非免疫原性和无毒的合成聚合物药物载体。连接到骨架上的是Geldanamycin类似物，其具有众所周知的双重作用模式（抗血管生成和抗肿瘤）和多西他赛，这是FDA批准的抗肿瘤剂，可通过稳定微管起作用。这些药物将通过溶酶体可降解的间隔物附着在骨架上，该垫片将允许细胞内释放和生物活性。 （3）含有配体的环状三肽，将HPMA偶联物靶向与肿瘤相关的受体。这种方法的新颖性是，geldanamycin的类似物和多西他赛的作用机理将连接到包含靶向部分的相同聚合物主链上，从而确保两种药物同时递送至癌细胞。 目的是三倍：（1）合成和生理化学表征HPMA共聚物与Geldanamycin类似物，多西他赛和侧链中的靶向三肽； （2）表征HPMA结合物的稳定性和释放曲线； （3）表征HPMA偶联物在卵巢癌细胞系中的结合性和细胞毒性。 该项目的最终目标是开发有效且可销售的药物与新型药物输送系统的治疗，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。 公共卫生相关性：本I阶段提案详细介绍了一个聚合物输送系统的合成和表征的基本原理和研究计划，该系统将同时将两种具有不同作用机制的抗癌药物交付到卵巢癌细胞中。这种组合疗法将最大程度地减少化学疗法的不良影响并最大化疗效，从而显着提高卵巢癌患者的五年生存率。