Targeted Polymeric Combination Delivery for Treatment of Ovarian Cancer

描述（由申请人提供）：本I期提案详细说明了聚合物递送系统的合成和表征的基本原理和研究计划，该系统将同时向卵巢癌细胞中递送两种具有不同作用机制的抗癌药物。递送系统将由N-（2-羟丙基）甲基丙烯酰胺（HPMA）共聚物作为骨架组成。它是一种充分表征的、水溶性的、生物相容的、非免疫原性的和无毒的合成聚合物药物载体。与骨架连接的是格尔德霉素类似物和多西他赛，格尔德霉素类似物具有众所周知的双重作用模式（抗血管生成和抗肿瘤），多西他赛是FDA批准的通过稳定微管起作用的抗肿瘤剂。药物将通过溶酶体可降解的间隔物连接到主链上，所述间隔物将允许细胞内释放和生物活性;和（3）含有环状三肽的配体，其将HPMA缀合物靶向肿瘤相关受体。这种方法的新奇在于，格尔德霉素类似物和多西他赛以其不同的作用机制将连接到含有靶向部分的相同聚合物主链上，从而确保将两种药物同时递送到癌细胞。 目标有三个方面：（1）合成并物理化学表征在侧链中具有格尔德霉素类似物、多西他赛和靶向三肽的HPMA共聚物;（2）表征HPMA缀合物的稳定性和释放曲线;和（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的和可销售的药物组合，用于治疗卵巢癌，其中药物位于肿瘤部位，化疗的副作用最小化，疗效最大化。 公共卫生相关性：该I期提案详细说明了聚合物递送系统的合成和表征的基本原理和研究计划，该聚合物递送系统将同时将两种具有不同作用机制的抗癌药物递送到卵巢癌细胞中。这种联合治疗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。

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.