Department of Biochemistry and Molecular Biology, Shanxi Medical University, Taiyuan, Shanxi, People's Republic of China,
Imaging Department of Shanxi Provincial Cancer Hospital, Shanxi Medical University, Imaging Department of Shanxi Medical University, Taiyuan, Shanxi, People's Republic of China,
Int J Nanomedicine. 2018 Jul 23;13:4333-4344. doi: 10.2147/IJN.S161908. eCollection 2018.
Effective endosomal escape is still a critical bottleneck for intracellular delivery of small interfering RNAs (siRNAs) to maximize their therapeutic efficacy. To overcome this obstacle, we have developed a photothermally triggered system by using the near-infrared (NIR) irradiation to achieve "on-demand" endosomal escape and subsequent siRNA release into cytoplasm.
Herein, the poly-L-lysine (PLL) was successfully conjugated with melanin to obtain melanin-poly-L-lysine (M-PLL) polymer as a siRNA vehicle. The melanin was an efficient photothermal sensitizer, and the positive pendant amino groups of PLL could condense siRNAs to form stable complexes by electrostatic interactions.
Inspired by its excellent photothermal conversion efficiency, the melanin was first involved in the siRNA delivery system. Confocal laser scanning microscopic observation revealed that after cellular uptake the photothermally induced endosomal escape could facilitate siRNAs to overcome endosomal barrier and be delivered into cytoplasm, which resulted in significant silence in the luciferase expression over the NIR- and melanin-free controls. Moreover, the anti-survivin siRNA-loaded M-PLL nanoparticles displayed great inhibitory effect on 4T1 tumor growth in vitro and in vivo.
These findings suggest that the M-PLL-mediated siRNA delivery is a promising candidate for therapeutic siRNA delivery and shows improved effect for cancer therapy via enhanced endosomal escape.
有效的内涵体逃逸仍然是将小干扰 RNA（siRNA）递送至细胞内以最大程度提高其治疗功效的关键瓶颈。为了克服这一障碍，我们开发了一种光热触发系统，该系统通过近红外（NIR）辐射实现“按需”内涵体逃逸，随后将 siRNA 释放到细胞质中。
在此，聚-L-赖氨酸（PLL）成功地与黑色素结合，获得黑色素-聚-L-赖氨酸（M-PLL）聚合物作为 siRNA 载体。黑色素是一种有效的光热敏化剂，PLL 的正电荷侧链氨基可以通过静电相互作用将 siRNAs 浓缩形成稳定的复合物。
受其优异的光热转换效率的启发，首先将黑色素纳入 siRNA 递药系统中。共焦激光扫描显微镜观察显示，细胞摄取后，光热诱导的内涵体逃逸可以促进 siRNAs 克服内涵体障碍并递送至细胞质中，从而导致荧光素酶表达显著沉默，超过了无 NIR 和黑色素对照。此外，载有抗生存素 siRNA 的 M-PLL 纳米颗粒在体外和体内对 4T1 肿瘤生长显示出巨大的抑制作用。
这些发现表明，M-PLL 介导的 siRNA 递药是治疗性 siRNA 递药的有前途的候选物，并通过增强内涵体逃逸显示出对癌症治疗的改善效果。
