Multifunctional Carriers for Systemic siRNA Delivery

描述（由申请人提供）：本研究项目的目标是设计和开发安全有效的多功能递送系统，用于系统和靶向性递送小干扰RNA (siRNA)，以RNA干扰（RNAi）治疗人类疾病。RNAi是一种基因沉默的自然机制，通过关闭特定的疾病相关基因来治疗人类疾病具有很大的潜力。最近的临床前和临床研究表明，用siRNA沉默基因可以有效治疗一系列人类疾病，包括癌症、病毒感染、眼病、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，siRNA的临床开发和使用受到限制。我们最近开发了一类新的多功能递送系统，其功能包括与siRNA形成纳米颗粒，pH敏感性两亲性，两亲性细胞膜在内体溶酶体pH下的破坏，环境响应性siRNA释放和特异性靶向，用于有效的全身和特异性体内siRNA递送。这个项目的具体目标是设计、合成和表征的系统性优化多功能运营商vivo交付的小干扰RNA和评价体外生物学性质的多功能运营商和肽有针对性的siRNA运载系统,包括细胞毒性,pH-sensitive细胞膜破坏,细胞吸收,endosomal-lysosomal逃脱,siRNA交付效率,以及一种具有模型治疗性siRNA、抗hif -1a siRNA的铅靶向递送系统的体内递送效率，以及它们在动物肿瘤模型中的抗癌治疗效果。与现有的siRNA传递系统相比，新型多功能siRNA传递系统具有更好的安全性和更高的体内siRNA传递特异性和效率。该项目的长期目标是开发安全、有效和特异性的siRNA递送系统，用于治疗人类疾病。

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.