siRNA delivery by structured polymers synthesized via combinatorial RAFT & ATRP

描述(由申请人提供)：我们建议开发自动化的组合ATRP和RAFT聚合技术，用于合成短链干扰RNA(SiRNA)传递的&gt；1500结构不同的核-壳多毛纳米粒的文库。这些聚合物将使用受控/活性自由基聚合(CRP)技术来合成，以实现对体系结构、分子量、多分散性和物理性能的控制。虽然siRNA具有治疗各种疾病的巨大潜力，但递送仍然是一个巨大的挑战，目前是阻碍siRNA商业化治疗疾病的关键障碍。因此，我们建议开发一个直径为10-80 nm的核壳毛状纳米粒子文库，一个阳离子核心，一个可调节和可功能化的外壳，用于siRNA的传递。高通量合成、纯化、相对分子质量和颗粒直径的测量、与siRNA的络合以及用于siRNA递送的体外筛选将连续进行。通过分析，我们预计将出现对络合和交付重要的结构基序。我们将通过对性能最佳的毛状纳米粒子的分析和比较来寻求了解结构与功能的关系。由于我们的方案采用组合、自动化的高通量合成和选择结构化聚合物来传递siRNA，因此所产生的材料具有克服传递和靶向挑战的潜力，这可能导致实现对各种疾病的治疗。 公共卫生相关性：短干扰RNA(SiRNA)具有治疗多种疾病的巨大潜力，包括癌症、关节炎、中枢神经系统疾病、视网膜病变、哮喘、帕金森病等，但传递仍然是阻碍siRNA成功用于治疗疾病的关键障碍。我们的建议采用组合、自动化的高通量合成和评估结构化聚合物，以控制siRNA传递的相对分子质量和结构。由此产生的聚合物具有克服传递和靶向挑战的潜力，这可能导致实现对各种疾病的治疗。

DESCRIPTION (provided by applicant): We propose to develop automated, combinatorial ATRP and RAFT polymerization techniques for the synthesis of a library of >1500 structurally distinct core-shell hairy nanoparticles for short interfering RNA (siRNA) delivery. The polymers will be synthesized using controlled/living radical polymerization (CRP) techniques to enable control over architecture, molecular weight, polydispersity, and physical properties. While siRNA has great therapeutic potential to treat various diseases, delivery remains a huge challenge and is at the present time, the key roadblock preventing commercialization of siRNA to treat disease. We therefore propose to develop a library of core-shell hairy nanoparticles with a diameter of 10-80 nm, a cationic core, and a tunable and functionalizable shell for siRNA delivery. High-throughput synthesis, purification, measurement of MW and particle diameter, complexation with siRNA, and in vitro screening for delivery of siRNA will be performed in series. Through analysis, we anticipate that structural motifs that are important for complexation and delivery will emerge. We will seek to understand structure-function relationships by analysis and comparison of the best performing hairy nanoparticles. As our proposal employs combinatorial, automated high-throughput synthesis and selection of structured polymers for siRNA delivery, the resulting materials have the potential to overcome delivery and targeting challenges, which may lead to realized therapies for various diseases. PUBLIC HEALTH RELEVANCE: Short interfering RNA (siRNA) has great therapeutic potential to treat various diseases including cancer, arthritis, CNS diseases, retinopathy, asthma, Parkinson's disease and others, but delivery remains as the key roadblock preventing successful utilization of siRNA to treat disease. Our proposal employs combinatorial, automated high-throughput synthesis and evaluation of structured polymers for with control over molecular weight and architecture for siRNA delivery. The resulting polymers have the potential to overcome delivery and targeting challenges, which may lead to realized therapies for various diseases.