Department of Biotechnology, Yonsei University, 50 Yonsei-ro, Seodaemun-guSeoul, 120-749, South Korea.
Department of Chemistry, The Graduate School of Nanoscience and Technology, Korea Advanced Institute of Science and Technology, 291 Daehak-ro, Yuseong-gu, Daejeon, 305-701, South Korea.
Adv Healthc Mater. 2016 Nov;5(22):2931-2941. doi: 10.1002/adhm.201600416. Epub 2016 Oct 24.
Small interfering RNA (siRNA) delivery can provide an effective therapy for treating viral diseases by silencing genes involved in viral replication. In this study, a liver-targeting formulation of lipidoid nanoparticle for delivery of siRNA that targets protein kinase C-related kinase 2 (PRK2) to inhibit hepatitis C virus (HCV) replication is reported. The most effective, minimally cytotoxic lipidoid for siRNA delivery to hepatic cells is identified from a small library of alkyl epoxide-polyamine conjugates. In vitro transfection of PRK2 siRNA (siPRK2) using this lipidoid induces significant silencing of PRK2 (≈80%), suppressing HCV replication in human hepatic cells transfected with the HCV subgenomic replicon. Systemic administration of siPRK2 using the lipidoid nanoparticles results in significant reduction of host PRK2 in the mouse liver (≈60%). This treatment significantly suppresses HCV replication in an HCV-xenograft mouse model. siRNA delivery to the liver is further improved via galactosylation of the lipidoid. Compared with the unmodified lipidoid formulation, galactosylated lipidoids induce greater silencing of host PRK2 in mouse livers (≈80%) and more rapid suppression of HCV replication in an HCV-xenograft mouse. This study suggests that galactosylated lipidoid nanoparticles could provide a treatment for hepatitis C by mediating delivery of anti-viral RNA interference therapeutics to the liver.
小干扰 RNA（siRNA）递呈可以通过沉默病毒复制相关基因来提供治疗病毒疾病的有效疗法。在这项研究中，报道了一种用于递送靶向蛋白激酶 C 相关激酶 2（PRK2）的 siRNA 的肝靶向脂质体纳米颗粒制剂，以抑制丙型肝炎病毒（HCV）复制。从小型烷基环氧化物-多胺缀合物文库中鉴定出最有效的、最小细胞毒性的用于肝细胞递呈 siRNA 的脂质体。使用这种脂质体转染 PRK2 siRNA（siPRK2）可诱导 PRK2 的显著沉默（≈80%），抑制转染 HCV 亚基因组复制子的人肝细胞中的 HCV 复制。使用脂质体纳米颗粒系统给予 siPRK2 可导致小鼠肝脏中宿主 PRK2 的显著减少（≈60%）。这种治疗可显著抑制 HCV 嵌合小鼠模型中的 HCV 复制。通过脂质体的半乳糖化进一步改善了 siRNA 向肝脏的递呈。与未修饰的脂质体制剂相比，半乳糖化脂质体在小鼠肝脏中诱导宿主 PRK2 的沉默更大（≈80%），并更快地抑制 HCV 嵌合小鼠中的 HCV 复制。本研究表明，半乳糖化脂质体纳米颗粒可通过介导抗病毒 RNA 干扰治疗剂递呈至肝脏，为丙型肝炎提供一种治疗方法。
