Hybrid nanotechnology to target metastatic advanced prostate cancer

描述（由申请人提供）：晚期恶性疾病，如去势抵抗性前列腺癌（CRPC）难以管理，因为这些癌症倾向于转移，并且通常对标准化疗反应不良。 RNA干扰（RNAi）疗法，例如小干扰RNA（siRNA），具有沉默关键分子途径以恢复癌症化学敏感性和减缓癌症扩散的高潜力。 我们的小组最近开发了新一代的混合纳米技术，以脂质-聚合物混合纳米载体（LPN）为代表，以低正常组织毒性有效地提供持续，受控的细胞内siRNA供应。使用LPN进行抗生存素-siRNA递送，我们报道了显著的RNAi化疗增敏作用在体外和体内延长的时间。我们的研究结果进一步表明，通过沉默生存素，我们能够基本上抑制CRPC的转移潜力。因此，LPN整合的RNAi疗法可以同时解决晚期CRPC的两个最具破坏性的问题。在本申请中，将使用靶向癌表面的LPN来实施这种有前途的疗法。具体而言，我们将（1）在转移性CRPC的原位模型中评估LPN的体内肿瘤靶向能力和药代动力学特性;（2）研究携带抗生存素siRNA的LPN的药效学和治疗特性，以优化CRPC化疗增敏和转移控制;（3）评价多西他赛联合携带抗survivin siRNA的LPN治疗CRPC的疗效。 与公共卫生相关。该项目的成功完成将验证和优化纳米技术整合的RNAi疗法，以防止晚期癌症扩散到健康组织，并使这些通常无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.