Gujrati Maneesh, Vaidya Amita, Lu Zheng-Rong
Department of Biomedical Engineering, Case Western Reserve University , Cleveland, Ohio 44106, United States.
Bioconjug Chem. 2016 Jan 20;27(1):19-35. doi: 10.1021/acs.bioconjchem.5b00538. Epub 2015 Dec 17.
RNA interference (RNAi) represents a powerful modality for human disease therapy that can regulate gene expression signature using small interfering RNA (siRNA). Successful delivery of siRNA into the cytoplasm of target cells is imperative for efficient RNAi and also constitutes the primary stumbling block in the clinical applicability of RNAi. Significant progress has been made in the development of lipid-based siRNA delivery systems, which have practical advantages like simple chemistry and easy formulation of nanoparticles with siRNA. This review discusses the recent development of pH-sensitive amino lipids, with particular focus on multifunctional pH-sensitive amino lipids for siRNA delivery. The key components of these multifunctional lipids include a protonatable amino head group, distal lipid tails, and two cross-linkable thiol groups, which together facilitate the facile formation of stable siRNA-nanoparticles, easy surface modification for target-specific delivery, endosomal escape in response to the pH decrease during subcellular trafficking, and reductive dissociation of the siRNA-nanoparticles for cytoplasmic release of free siRNA. By virtue of these properties, multifunctional pH-sensitive lipids can mediate efficient cytosolic siRNA delivery and gene silencing. Targeted siRNA nanoparticles can be readily formulated with these lipids, without the need for other helper lipids, to promote systemic delivery of therapeutic siRNAs. Such targeted siRNA nanoparticles have been shown to effectively regulate the expression of cancer-related genes, resulting in significant efficacy in the treatment of aggressive tumors, including metastatic triple negative breast cancer. These multifunctional pH-sensitive lipids constitute a promising platform for the systemic and targeted delivery of therapeutic siRNA for the treatment of human diseases. This review summarizes the structure-property relationship of the multifunctional pH-sensitive lipids and their efficacy in in vitro and in vivo siRNA delivery and gene silencing.
RNA干扰（RNAi）是一种用于人类疾病治疗的强大手段，它可以利用小干扰RNA（siRNA）来调控基因表达特征。将siRNA成功递送至靶细胞的细胞质对于有效的RNAi至关重要，同时也是RNAi临床应用的主要绊脚石。基于脂质的siRNA递送系统的开发已取得显著进展，这类系统具有化学组成简单以及易于将纳米颗粒与siRNA进行制剂等实际优势。本综述讨论了pH敏感型氨基脂质的最新进展，尤其关注用于siRNA递送的多功能pH敏感型氨基脂质。这些多功能脂质的关键组成部分包括一个可质子化的氨基头部基团、远端脂质尾部以及两个可交联的硫醇基团，它们共同促进了稳定的siRNA纳米颗粒的轻松形成、易于进行表面修饰以实现靶向递送、在亚细胞运输过程中响应pH降低实现内体逃逸，以及siRNA纳米颗粒的还原解离以释放游离siRNA至细胞质。凭借这些特性，多功能pH敏感型脂质可以介导有效的细胞溶质siRNA递送和基因沉默。使用这些脂质可以轻松制备靶向siRNA纳米颗粒，无需其他辅助脂质，以促进治疗性siRNA的全身递送。已证明这类靶向siRNA纳米颗粒能够有效调节癌症相关基因的表达，在治疗侵袭性肿瘤（包括转移性三阴性乳腺癌）方面具有显著疗效。这些多功能pH敏感型脂质构成了一个有前景的平台，用于治疗人类疾病的治疗性siRNA的全身和靶向递送。本综述总结了多功能pH敏感型脂质的结构-性质关系及其在体外和体内siRNA递送及基因沉默中的功效。
