Development of nucleic acid delivery platform based on polymeric CXCR4 antagonists

 描述(由申请人提供)：基于核酸(NA)的治疗方法有望彻底改变多种疾病的治疗方法，但目前由于缺乏有效的给药方法，其广泛使用受到限制。我们最近开发了一种基于聚合物CXCR4抑制剂(PCX)的新的NA递送平台，适用于同时递送NA和抑制CXCR4趋化因子受体的双功能系统。这个为期一年的第一阶段项目的目标是利用PCX平台开发一种使用PCX/microRNA纳米颗粒的创新联合治疗胆管癌。临床和实验研究表明，CXCR4的表达与胆管细胞癌更具侵袭性、更高的原发肿瘤负担、更多的转移和更短的总生存期有关。本项目的假设是，使用PCX递送miR106b抑制剂，这是我们的初步研究中确定的S胆管癌细胞的潜在靶点，将导致整体抗癌活性的提高。我们将通过追求以下特定目标来实现这些目标：1)优化PCX/microRNA处方参数，以获得能够同时抑制CXCR4和在胆管癌细胞中传递microRNA的纳米颗粒；2)确定PCX传递miR106b抑制剂是否提高了原位胆管癌细胞模型大鼠的总存活率。该方法具有创新性，因为纳米颗粒具有CXCR4抑制活性和microRNA递送的双重功能。这项拟议的研究具有重要意义，因为它将建立广泛适用和多功能的NA递送平台，以趋化因子网络为靶点，作为一种改善癌症和其他涉及CXCR4的疾病的治疗结果的方式。

 DESCRIPTION (provided by applicant): Therapeutics based on nucleic acids (NA) promise to revolutionize treatment of multiple diseases but their widespread use is currently limited by the lack of efficient delivery methods. We have recently developed a new NA delivery platform based on polymeric CXCR4 inhibitors (PCX) suitable as dual-function systems for simultaneous NA delivery and inhibition of CXCR4 chemokine receptor. The objective of this 1-year Phase I project is to use the PCX platform to develop an innovative combination treatment of cholangiocarcinoma using PCX/microRNA nanoparticles. Clinical and experimental studies show that CXCR4 expression is associated with more aggressive disease, higher primary tumor burden, more metastases, and shorter overall survival in cholangiocarcinoma. The hypothesis of this project is that using PCX to deliver miR106b inhibitor, identified in our preliminary studies s potential target in cholangiocarcinoma, will lead to improved overall anticancer activity. We will accomplish the objectives through pursuing the following specific aims: 1) optimize PCX/microRNA formulation parameters to obtain nanoparticles capable of simultaneous CXCR4 inhibition and microRNA delivery in cholangiocarcinoma and 2) determine if delivery of miR106b inhibitor by PCX improves overall survival in orthotopic rat model of cholangiocarcinoma. The approach is innovative because of the dual-function design of nanoparticles with CXCR4 inhibitory activity and microRNA delivery. The proposed research is significant because it will establish widely applicable and versatile NA delivery platform that target chemokine networks as a way of improving therapeutic outcomes in cancer and other diseases with involvement of CXCR4.