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）：该第一阶段提案详细介绍了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输送到卵巢癌细胞中。该递送系统将由N-(2-羟丙基)甲基丙烯酰胺(HPMA)共聚物作为主链组成。它是一种性质良好、水溶性、生物相容性、非免疫原性、无毒的合成高分子药物载体。附着在骨架上的是格尔德霉素类似物，它具有众所周知的双重作用模式（抗血管生成和抗肿瘤）和多西紫杉醇，多西紫杉醇是 FDA 批准的抗肿瘤药物，通过稳定微管发挥作用。这些药物将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； (3) 含有配体的环状三肽，该配体将 HPMA 缀合物靶向肿瘤相关受体。这种方法的新颖之处在于，格尔德霉素类似物和多西紫杉醇具有不同的作用机制，将附着在含有靶向部分的同一聚合物主链上，从而确保两种药物同时递送至癌细胞。 目标有三个：(1) 合成侧链带有格尔德霉素类似物、多西紫杉醇和靶向三肽的 HPMA 共聚物，并对其进行物理化学表征； (2) 表征 HPMA 缀合物的稳定性和释放曲线； (3)通过生物学方法表征HPMA缀合物在卵巢癌细胞系中的结合和细胞毒性。 该项目的最终目标是开发一种有效且可销售的药物组合，与新型药物递送系统一起治疗卵巢癌，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。 公共健康相关性：这一第一阶段提案详细介绍了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输送到卵巢癌细胞中。这种联合疗法将最大限度地减少化疗的副作用并最大限度地提高疗效，从而显着提高卵巢癌患者的五年生存率。