Targeted Polymeric Combination Delivery for Treatment of Ovarian Cancer

描述(由申请人提供)：这项第一阶段的提案详细说明了合成和表征一种聚合物递送系统的原理和研究计划，该系统将同时向卵巢癌细胞递送两种具有不同作用机制的抗癌药物。给药系统将以N-(2-羟丙基)甲基丙烯酰胺(HPMA)共聚物为骨架。它是一种具有良好特性、水溶性、生物相容性、无免疫原性、无毒的合成聚合物药物载体。连接到主干上的是一种格尔达霉素类似物，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批准的一种通过稳定微管发挥作用的抗肿瘤药物。这些药物将通过溶酶体可降解的间隔物连接到骨架上，该间隔物将允许细胞内释放和生物活性；以及(3)含有将靶向肿瘤相关受体的HPMA偶联物的配体的环状三肽。这种方法的新奇之处在于，具有不同作用机制的格尔达霉素类似物和多西紫杉醇将连接到含有靶向部分的同一聚合物骨架上，从而确保两种药物同时输送到癌细胞。本研究的目的有三个方面：(1)合成和理化表征侧链上含有格尔丹霉素类似物、多西紫杉醇和靶向三肽的HPMA共聚物；(2)表征HPMA结合物的稳定性和释放度；(3)用生物学方法研究HPMA结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的、有市场价值的药物组合和新型给药系统用于卵巢癌的治疗，其中药物定位于肿瘤部位，最大限度地减少化疗的不良反应，并使疗效最大化。 与公共健康相关：这项第一阶段的提案详细说明了合成和表征聚合物递送系统的基本原理和研究计划，该系统将同时向卵巢癌细胞递送两种具有不同作用机制的抗癌药物。这种联合疗法将最大限度地减少化疗的不良反应，最大限度地提高疗效，从而显著提高卵巢癌患者的五年生存率。

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.