Hybrid nanotechnology to target metastatic advanced prostate cancer

描述(申请人提供)：晚期恶性疾病，如去势抵抗型前列腺癌(CRPC)，很难治疗，因为这些癌症容易转移，而且对标准化疗的反应通常很差。RNA干扰(RNAi)疗法，如小干扰RNAs(SiRNAs)，具有很高的沉默关键分子通路的潜力，以恢复癌症的化疗敏感性，减缓癌症的扩散。我们团队最近开发了以脂质-聚合物杂化纳米载体(LPN)为代表的新一代杂化纳米技术，以提供持续、可控的细胞内siRNA供应，同时正常组织毒性较低。使用LPN作为抗Survivin-siRNA的载体，我们在体外和体内都发现了显著的RNAi化疗增敏作用。我们的结果进一步证明，通过沉默Survivin，我们能够显著抑制CRPC的转移潜能。因此，LPN整合的RNAi疗法可能同时解决晚期CRPC最具破坏性的两个问题。在这项应用中，这一有希望的疗法将使用癌症表面靶向LPN来实施。具体地说，我们将(1)在转移性CRPC原位模型中评估LPN的体内肿瘤靶向能力和药代动力学特性；(2)研究携带抗Survivin siRNA的LPN的药效学和治疗特性，以优化CRPC的化疗增敏和转移控制；(3)评估由多西紫杉醇和携带抗Survivin siRNA的LPN联合治疗CRPC的疗效。与公共卫生的相关性。该项目的成功完成将验证和优化一种纳米技术集成的RNAi疗法，以防止晚期癌症扩散到健康组织，并使这些通常没有反应的癌症再次对标准药物治疗产生反应。

DESCRIPTION (provided by applicant): Advanced malignant diseases such as castration-resistant prostate cancer (CRPC) are difficult to manage because these cancers tend to metastasize and are often poorly responsive to the standard chemotherapy. RNA-interference (RNAi) therapeutics, e.g. small-interfering RNAs (siRNAs), hold high potential for silencing critical molecular pathways to restore the cancer chemosensitivity and slow down the spread of cancer. Our group has recently developed a new generation of hybrid nanotechnology, represented by lipid-polymer hybrid nanocarrier (LPN), to provide sustained, controlled intracellular siRNA supply efficiently at low normal tissue toxicity. Using LPN for anti-survivin-siRNA delivery, we reported significant RNAi-chemosensitization in vitro and in vivo for extended time. Our results further demonstrated that by silencing survivin, we were able to substantially suppress the metastatic potential of CRPC. LPN-integrated RNAi-therapy therefore may simultaneously tackle the two most devastating problems of advanced CRPC. In this application, this promising therapy will be implemented using a cancer-surface targeting LPN. Specifically, we will (1) evaluate the in vivo tumor-targeting capabilities and pharmacokinetic properties of LPN in an orthotopic model of metastatic CRPC; (2) study the pharmacodynamic and therapeutic properties of LPN carrying anti-survivin siRNA for optimal CRPC chemosensitization and control of metastasis; (3) evaluate the therapeutic outcomes of chemo-RNAi combination therapy consisting of docetaxel and LPN carrying anti-survivin siRNA for CRPC treatment. Relevance to Public Health. Successful completion of this project will validate and optimize a nanotechnology-integrated RNAi-therapy for preventing advanced-stage cancers from spreading to the healthy tissues, and turning these often non-responsive cancers responsive to the standard drug treatment again.