siRNA delivery by structured polymers synthesized via combinatorial RAFT & ATRP

通过组合 RAFT 合成的结构化聚合物进行 siRNA 递送

• 批准号: 8058068
• 负责人: Daniel John Siegwart
• 金额: $ 5.13万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-02-01 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8058068
• 关键词: Architecture; Arthritis; Asthma; Caliber; Central Nervous System Diseases; Development; Disease; Evaluation; In Vitro; Lead; Libraries; Life; Malignant Neoplasms; Measurement; Methods; Molecular Weight; Parkinson Disease; Polymers; RNA; Retinal Diseases; Screening procedure; Series; Structure; Structure-Activity Relationship; Techniques; Therapeutic; Time; combinatorial; commercialization; nanoparticle; particle; physical property; polymerization; prevent; targeted delivery

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.

描述（由申请人提供）：我们建议开发自动化的，组合的ATRP和筏聚合技术，用于合成> 1500> 1500的库中> 1500的库中核心壳毛状纳米颗粒，以用于短暂干扰RNA（siRNA）。聚合物将使用受控/活的自由基聚合（CRP）技术合成，以控制建筑，分子量，多分散性和物理特性。尽管siRNA具有治疗各种疾病的巨大治疗潜力，但分娩仍然是一个巨大的挑战，目前是阻止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，阳离子芯和可调且可调的壳的核心壳毛纳米颗粒库，用于siRNA递送。高通量合成，MW和颗粒直径的纯化，测量，与siRNA的络合以及siRNA递送的体外筛选。通过分析，我们预计对于络合和传递至关重要的结构基序将出现。我们将寻求通过分析和比较最佳性能毛纳米颗粒来理解结构功能关系。由于我们的提案采用了组合，自动化的高通量合成和用于siRNA递送的结构化聚合物的选择，因此所得材料有可能克服交付和靶向挑战，这可能会导致各种疾病的实现疗法。 公共卫生相关性：简短干扰RNA（siRNA）具有治疗各种疾病的巨大治疗潜力，包括癌症，关节炎，中枢神经系统疾病，视网膜病变，哮喘，帕金森氏病等，但仍是阻止成功利用siRNA治疗疾病的关键路线。我们的提案采用组合，自动化的高通量合成和对结构化聚合物的评估，以控制分子量和siRNA递送的分子量和结构。由此产生的聚合物有可能克服交付和靶向挑战，这可能会导致对各种疾病的实现疗法。