Targeted polymeric nanocarriers for combination therapy of metastatic prostate ca

描述（由申请人提供）：前列腺癌是美国男性癌症死亡的第二大原因。局限性前列腺癌是高度可治疗的，而转移性前列腺癌的5年生存率为33%。我们研究的长期目标是开发靶向、联合基因和药物递送的纳米载体，用于治疗转移性前列腺癌。本研究的目标是：1)设计和合成聚合物纳米载体，用于同时递送小分子抗癌前药格尔达霉素和编码肿瘤坏死因子相关凋亡诱导配体（TRAIL）的基因；2)开发一种靶向her2的基于PEG的屏蔽，将载体定位在肿瘤细胞中，并从细胞内的纳米载体中释放出来，允许DNA递送到细胞核。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。我们的理由是，通过利用TRAIL和格尔达霉素的已知协同作用，确保将药物和DNA结合在一个载体上递送到肿瘤细胞，将最大限度地提高治疗效果。内核体pH触发释放屏蔽和HER2/neu靶向/内化肽的添加将最大化肿瘤的传递和内化，同时最小化对非靶组织的毒性。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，最大限度地扩大了治疗窗口。

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.