Polymer-drug Conjugate Micelles for Treating Resistant Prostate Cancers

描述(由申请人提供)：紫杉烷(如多西紫杉醇)已被用作雄激素非依赖性前列腺癌的标准治疗方法。然而，许多患者由于多药耐药(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，它集成了药物发现、癌症治疗和基于纳米技术的药物输送方面的多种创新。首先，我们将使用一种新型的微管抑制剂，4-取代甲氧基苯甲酰-芳基噻唑-100(SMART)，以克服前列腺癌的多药耐药。第二，多功能聚合物-药物结合物(PDC)胶束将被用于靶向将SMART输送到前列腺癌。PDC胶束的独特设计使前列腺癌特异性药物能够通过增强的渗透性和滞留(EPR)效应以及通过肿瘤靶向肽的主动肿瘤靶向传递。核心假设是肿瘤靶向pH响应型聚合物-药物偶联物(PDC)胶束可以增强智能药物对前列腺癌细胞的转运，并通过诱导细胞周期停滞和细胞凋亡来有效治疗多药耐药前列腺癌。我们将研究以下具体目标：(1)合成pH响应型聚合物药物结合物胶束，用于SMART的传递；(2)制备靶向多肽修饰的PDC胶束，用于前列腺癌靶向；(3)评价SMART PDC胶束与MDR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.