Multifunctional Carriers for Systemic siRNA Delivery

描述（由申请人提供）：本研究项目的目的是设计和开发安全有效的多功能递送系统，用于小干扰RNA（siRNA）的全身性和靶向特异性递送，以通过RNA干扰（RNAi）治疗人类疾病。RNAi是一种基因沉默的天然机制，具有通过关闭特定疾病相关基因来治疗人类疾病的巨大潜力。最近的临床前和临床研究已经证明，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，siRNA的临床开发和使用受到缺乏安全有效的体内递送系统的限制。我们最近开发了一类新的多功能递送系统，其具有与siRNA形成纳米颗粒、pH敏感的两亲性、特异性在内体-溶酶体pH下的两亲性细胞膜破坏、环境响应性siRNA释放和特异性靶向的功能，用于有效的全身性和特异性体内siRNA递送。本项目的具体目标是设计、合成和表征用于小干扰RNA的系统性体内递送的优化的多功能载体，并评估多功能载体和肽靶向siRNA递送系统的体外生物学性质，包括细胞毒性、pH敏感性细胞膜破坏、细胞摄取、内体-溶酶体逃逸、siRNA递送效率、和具有模型治疗性siRNA、抗HIF-1a siRNA的先导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功效。与目前可用的siRNA递送系统相比，新的多功能siRNA递送系统将具有更好的安全性特征以及更高的体内siRNA递送特异性和效率。该项目的长期目标是开发安全、有效和特异性的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目前可用的治疗方法无法有效治疗的一系列人类疾病。具有更好的安全性和高递送效率的新型递送系统将通过将用于基因调控的效应物特异性递送到其靶点来促进这种新治疗的临床开发和应用。

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.