Multifunctional Carriers for Systemic siRNA Delivery

描述(申请人提供)：本研究项目的目标是设计和开发安全高效的多功能递送系统，用于系统性和靶向性地递送小干扰RNA(SiRNA)，以利用RNA干扰(RNAi)治疗人类疾病。RNAi是一种自然的基因沉默机制，通过关闭特定的疾病相关基因来治疗人类疾病具有巨大的潜力。最近的临床前和临床研究表明，用siRNA进行基因沉默可以有效地治疗一系列人类疾病，包括癌症、病毒感染、眼部疾病、自身免疫性疾病和神经系统疾病。然而，由于缺乏安全有效的体内递送系统，限制了siRNA的临床开发和应用。我们最近开发了一类新型的多功能递送系统，具有与siRNA形成纳米颗粒、pH敏感的两亲性、两亲细胞膜的破坏、环境响应性siRNA释放和特异性靶向等功能，以实现高效的系统和体内特异性的siRNA递送。本项目的具体目的是设计、合成和表征优化的多功能载体，用于系统体内传递小干扰RNA，并评价多功能载体和多肽靶向siRNA传递系统的体外生物学特性，包括细胞毒性、对pH敏感的细胞膜破坏、细胞摄取、内毒素-溶酶体逃逸、siRNA传递效率、带有模型治疗性siRNA的铅靶向传递系统的体内传递效率、抗HIF-1a siRNA，以及它们在动物肿瘤模型中的抗癌治疗效果。与现有的siRNA递送系统相比，新型多功能siRNA递送系统将具有更好的安全性、更高的体内siRNA递送特异性和效率。该项目的长期目标是开发安全、高效和特异的siRNA递送系统，用于治疗人类疾病。 公共卫生相关性：关闭疾病相关基因有望治疗一系列目前可用的治疗方法无法有效治疗的人类疾病。新型的给药系统具有更好的安全性和更高的给药效率，通过将基因调控的效应器特异性地输送到靶点，将促进这一新疗法的临床开发和应用。

DESCRIPTION (provided by applicant): The objectives of this research project are to design and develop safe and efficient multifunctional delivery systems for systemic and target-specific delivery of small interfering RNA (siRNA) to treat human diseases with RNA interference (RNAi). RNAi is a natural mechanism for gene silencing and has a great potential to treat human disease by turning off specific disease related genes. Recent preclinical and clinical studies have demonstrated that gene silencing with siRNA can be effective to treat a spectrum of human diseases, including cancer, viral infections, ocular diseases, autoimmune diseases and neurological disorders. However, clinical development and use of siRNA are limited by the lack of safe and efficient in vivo delivery systems. We have recently developed a novel class of multifunctional delivery systems with the functionalities of nanoparticle formation with siRNA, pH-sensitive amphiphilicity, amphiphilic cell membrane disruption specifically at the endosomal-lysosomal pH, environment-responsive siRNA release and specific targeting, for efficient systemic and specific in vivo siRNA delivery. The specific aims of this project are to design, synthesize and characterize optimized multifunctional carriers for systemic in vivo delivery of small interfering RNA and to evaluate in vitro biological properties of the multifunctional carriers and peptide targeted siRNA delivery systems, including cytotoxicity, pH-sensitive cell membrane disruption, cell uptake, endosomal-lysosomal escape, siRNA delivery efficiency, and in vivo delivery efficiency of a lead targeted delivery system with a model therapeutic siRNA, anti-HIF-1a siRNA, and their efficacy of anti-cancer treatment in animal tumor models. The novel multifunctional siRNA delivery system will have better safety profiles and higher specificity and efficiency for in vivo siRNA delivery than currently available siRNA delivery systems. The long-term goal of this project is to develop safe, efficient and specific delivery systems of siRNA for the treatment of human diseases. PUBLIC HEALTH RELEVANCE: Turning off disease related genes is promising to treat a spectrum of human diseases that cannot be efficaciously treated with currently available treatment methods. Novel delivery systems with better safety profiles and high delivery efficiency will facilitate the clinical development and application of this new treatment by specific delivery of the effectors for gene regulation into their targets.