基于成像监测的抗肿瘤药物与siRNA共传递多功能靶向控释系统

The outcome of this project will be a multifunctional polymeric carrier system for the optical image-guided co-delivery of siRNA and small molecular drugs. One of the major significances of this project is that the NIR fluorescence of proposed delivery system can be turned “Off” or “On” by assembling or disassembling the complex. When assembled, fluorescence will be quenched due to the aggregation of fluorophores in the hydrophobic core of intact micelles-drug complexes during transport, and it will be recovered when the distribution of fluorophores into cytosol happens with the degradation of nanostructures after penetration into cells. To achieve this, an amphipathic block co-polymer carrying multiple Cyanine-7 fluorophores in its hydrophobic block will be synthesized by living polymerization. After the modification of cancer cell targeting groups at the end of hydrophilic blocks, these amphipathic copolymers will be assembled with amphipathic polypeptides, small molecular drugs and siRNAs to form a micelle-drug complex. The multifunctional drug co-delivery system will be further validated by using hydroxycamptothecin (HCPT) and Bcl-xL siRNA as the combination model. The biodistribution and function of these complexes in cells and animals will be detected and evaluated in real time by NIR imaging. Based on the result of imaging and biological analysis, the physical characters of complex, as well as the combination of drug and siRNA, and the targeting groups will be screened and optimized for the most efficient therapeutics to a specific cancer or cell line. It will promote the accurate treatment.

本项目旨在构建一种能够用近红外成像的方法来监测siRNA和小分子药物共传递的靶向控释 载体系统。其主要特色在于采用生物相容的两性嵌段共聚物构建 “智能”胶束纳米体系，利用近红外荧光基团在胶束内部的自淬灭效应使复合体系的荧光处于“关闭”状态；而在靶点细胞内进行药物释放的同时，荧光则处于“打开”的状态。首先用活性聚合方法获得在疏水段具有多个Cy7荧光基团的两亲性高分子嵌段共聚物，在其上修饰肿瘤细胞靶向基团，将它们与两亲性寡肽以及小分子疏水药物和siRNA共同组装成胶束药物复合体。研究中将主要以羟基喜树碱和Bcl-xL siRNA为组合模式来验证该多功能靶向控释系统的特性。分别在细胞和模式动物活体中用红外成像实时检测复合体的转运、靶向分布、药物释放过程和细胞响应状态。根据体外和体外实验结果调整优化胶束复合体的结构和靶向基团，并针对不同肿瘤细胞筛选药物和siRNA的最佳组合,促进抗肿瘤的精准治疗。

本项目旨在构建一种能够用近红外成像的方法来监测siRNA和小分子药物共传递的靶向控释 载体系统。其主要特色在于采用生物相容的两性嵌段共聚物构建 “智能”胶束纳米体系，利用近红外荧光基团在胶束内部的自淬灭效应使复合体系的荧光处于“关闭”状态；而在靶点细胞内进行药物释放的同时，荧光则处于“打开”的状态。首先用活性聚合方法获得在疏水段具有多个荧光基团的两亲性高分子嵌段共聚物，在其上修饰肿瘤细胞靶向基团，将它们与两亲性寡肽以及小分子疏水药物和siRNA共同组装成胶束药物复合体。研究中将主要以羟基喜树碱和Bcl-xL siRNA为组合模式来验证该多功能靶向控释系统的特性。分别在细胞和模式动物活体中用红外成像实时检测复合体的转运、靶向分布、药物释放过程和细胞响应状态。根据体外和体外实验结果调整优化胶束复合体的结构和靶向基团，并针对不同肿瘤细胞筛选药物和siRNA的最佳组合,促进抗肿瘤的精准治疗。