siRNA delivery by structured polymers synthesized via combinatorial RAFT & ATRP

描述（由申请人提供）：我们提出开发自动化的组合ATRP和RAFT聚合技术，用于合成用于短干扰RNA（siRNA）递送的>1500个结构上不同的核-壳毛状纳米颗粒的文库。聚合物将使用受控/活性自由基聚合（CRP）技术合成，以控制结构，分子量，多分散性和物理性能。虽然siRNA具有治疗各种疾病的巨大治疗潜力，但递送仍然是一个巨大的挑战，并且目前是阻止siRNA商业化以治疗疾病的关键障碍。因此，我们建议开发一个具有直径为10-80 nm的核-壳毛状纳米颗粒、阳离子核和可调且可官能化的壳的文库，用于siRNA递送。将连续进行高通量合成、纯化、MW和粒径测量、与siRNA复合以及siRNA递送的体外筛选。通过分析，我们预计，复杂和交付的重要结构图案将出现。我们将通过分析和比较表现最好的毛状纳米颗粒来寻求理解结构-功能关系。由于我们的建议采用组合，自动化高通量合成和选择用于siRNA递送的结构化聚合物，因此所得材料具有克服递送和靶向挑战的潜力，这可能导致实现各种疾病的治疗。 公共卫生相关性：短干扰RNA（siRNA）在治疗包括癌症、关节炎、中枢神经系统疾病、视网膜病、哮喘、帕金森病等在内的各种疾病方面具有巨大的治疗潜力，但递送仍然是阻碍siRNA成功用于治疗疾病的关键障碍。我们的建议采用组合的，自动化的高通量合成和结构化聚合物的评价，以控制分子量和siRNA递送的结构。由此产生的聚合物具有克服递送和靶向挑战的潜力，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.