Targeted polymeric nanocarriers for combination therapy of prostate cancer

描述(申请人提供)：前列腺癌是美国男性癌症死亡的第二大原因。虽然局限性前列腺癌是高度可治疗的，但转移性前列腺癌的5年存活率为33%。我们研究的长期目标是开发靶向的、组合的基因和药物传递纳米载体来治疗转移性前列腺癌。本研究的目的是1)设计和合成可同时传递格尔达霉素小分子抗癌前药和肿瘤坏死因子相关的凋亡诱导配体(TRAIL)基因的聚合物纳米载体，2)开发基于HER2的聚乙二醇靶向屏蔽剂，它将载体定位在肿瘤细胞中并从纳米载体细胞内释放，从而使DNA能够传递到细胞核中，以及3)确定这些纳米载体在前列腺癌啮齿动物模型中的药代动力学和处置。我们的理性是，通过利用TRAIL和格尔达霉素的已知协同作用，并确保两者都能传递到肿瘤细胞，在单一载体中结合药物和DNA将使治疗效益最大化。添加内体pH触发释放屏蔽物和HER2/neu靶向/内化多肽将最大限度地提高肿瘤的递送和内化，同时将对非靶组织的毒性降至最低。最后，这些药物对正常组织几乎没有毒性，限制了可能的副作用，并最大化了治疗窗口。 项目简介：这项研究是一种通过开发HER2靶向疗法来改善人类健康的创新方法，该疗法结合了基因和药物治疗转移性前列腺癌。我们将使用一种仅针对转移性前列腺癌细胞的纳米药物/基因载体。如果成功，这将为HER2+前列腺癌的治疗提供一个新的平台，HER2+前列腺癌是一种侵袭性表型，存在于80%的高转移性激素难治性前列腺癌中。

DESCRIPTION (provided by applicant): Prostate cancer is the second leading cause of cancer mortality in American men. Whereas localized prostate cancer is highly treatable, metastasized prostate cancer has a 5-year survival rate of 33%. The long term goal of our research is to develop targeted, combination gene and drug delivery nanocarriers for treatment of metastatic prostate cancers. The objectives of this study are to 1) design and synthesize polymeric nanocarriers for simultaneous delivery of a small-molecule anti-cancer prodrug of geldanamycin and a gene encoding tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), 2) develop a HER2-targeted PEG- based shield that will localize carriers in tumor cells and release from the nanocarrier intracellularly to allow DNA delivery to the nucleus, and 3) determine the pharmacokinetics and disposition of these nanocarriers in rodent models of prostate cancer. Our rational is combination of drug and DNA delivery in a single carrier will maximize therapeutic benefit by utilizing the known synergy of TRAIL and geldanamycin, and by ensuring delivery of both to a tumor cells. The addition of an endosome pH triggered-release shield and HER2/neu targeting/internalization peptide will maximize tumor delivery and internalization, while minimizing toxicity to non- target tissues. Finally, these agents have little or no toxicity to normal tissues, limiting the possible side-effects and maximizing the therapeutic window. Project Narrative: This study is an innovative approach to improving human health by developing a HER2 targeted therapy for treating metastatic prostate cancer with a combination of gene and drug therapy. We will use a nanoscopic drug/gene carrier that targets only metastatic prostate cancer cells. If successful, this will provide a new platform for building treatments for HER2+ prostate cancers, an aggressive phenotype present in >80% of highly metastatic hormone refractory prostate tumors.