Polymer-drug Conjugate Micelles for Treating Resistant Prostate Cancers

描述（由申请人提供）：紫杉烷类（如多西他赛）已被用作雄激素非依赖性前列腺癌的标准治疗。然而，许多患者由于多重耐药（MDR）的发展而复发，导致预后不良。为了应对这一挑战，我们建议开发一种聚合物纳米药物，该药物在药物发现、癌症治疗和基于纳米技术的药物传递方面集成了多种创新。首先，我们将使用一种新型微管抑制剂，4-取代甲氧基苯甲酰芳基噻唑-100 (SMART)，来克服前列腺癌的耐多药耐药。其次，利用多功能聚合物-药物偶联（PDC）胶束靶向给药SMART进入前列腺癌。PDC胶束的独特设计使前列腺癌特异性药物通过增强渗透性和保留（EPR）效应和通过肿瘤靶向肽的活性肿瘤靶向传递。核心假设是肿瘤靶向ph反应性聚合物-药物偶联物（PDC）胶束可以增强SMART药物向前列腺癌细胞的传递，并通过诱导细胞周期阻滞和细胞凋亡有效治疗耐多药前列腺癌。以下具体目标将被研究：(1)合成ph响应聚合物-药物共轭胶束用于传递SMART；(2)制备靶向肽修饰PDC胶束用于前列腺癌靶向；(3)评价SMART PDC胶束对耐多药前列腺癌细胞的抗癌作用。

DESCRIPTION (provided by applicant): Taxanes (e.g. docetaxel) have been used to as standard treatments for androgen-independent prostate cancer. However, many patients relapse due to the development of multiple drug resistance (MDR), which results in poor prognosis. To address this challenge, we propose to develop a polymeric nanomedicine which has integrated multiple innovations in drug discovery, cancer therapy and nanotechnology-based drug delivery. First, we will use a novel microtubule inhibitor, 4-substituted methoxybenzoyl-aryl-thiazole-100 (SMART), to overcome MDR in prostate cancers. Second, multifunctional polymer-drug conjugate (PDC) micelles will be utilized to targeted deliver SMART into prostate cancers. The unique design of PDC micelles enables prostate cancer specific drug delivery through both enhanced permeability and retention (EPR) effects and active tumor targeting via tumor targeting peptides. The central hypothesis is that tumor targeting pH-responsive polymer- drug conjugate (PDC) micelles can enhance the delivery of SMART drugs into prostate cancer cells and effectively treat MDR prostate cancers by inducing cell cycle arrest and apoptosis. The following specific aims will be investigated: (1) Synthesize pH-responsive Polymer-drug Conjugate Micelles for the Delivery of SMART; (2) Prepare Targeting Peptide Decorated PDC micelles for Prostate Cancer Targeting; (3) Evaluate Anticancer Effects of SMART PDC micelles with MDR Prostate Cancer cells.