State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China.
Department of Pharmaceutics, Guizhou Medical University, Huaxi university town, Guian new district 550025 Guizhou, People's Republic of China.
ACS Appl Mater Interfaces. 2020 Apr 1;12(13):14770-14783. doi: 10.1021/acsami.9b19373. Epub 2020 Mar 18.
Despite the great potential of combination therapy based on siRNA and chemotherapeutics, an efficient vehicle with abilities of well drug co-loading, synchronizing trafficking, and target-specific co-burst release remains elusive, which results in a suboptimal synergistic potency. Herein, a novel chitosan amphiphile (PEI-ss-HECS-ss-OA, HSPO) with glutathione (GSH)-reversible cationization and hydrophobicization by polyethylenimine (PEI) and octylamine (OA), respectively, was developed for this purpose. HSPO spontaneously assembled in aqueous solution to be a micellar system and effectively co-encapsulated the two drugs with an adjustable dosage ratio. With a surface charge inversion strategy by hyaluronic acid (HA) coating, the HA(HSPO) co-delivery micelles with a negative surface charge (-21.45 ± 1.44 mV) and suitable size (192.52 ± 7.41 nm) selectively accumulated into CD44 overexpressed A549 tumors through a combination of passive and active targeting mechanism. Then, tumor cytoplasm-selective co-burst release was obtained through GSH triggered collapse of the amphiphilic assembly alongside a decrease of positive charge condensation, finally leading to an enhanced synergistic antitumor effect with a superior inhibition ratio of 86.63%. Overall, this study validated the great promise of HSPO as an efficient site-specific rapid co-trafficking vehicle of siRNA and chemotherapeutics for a remarkable synergistic tumor inhibition.
尽管基于 siRNA 和化疗药物的联合治疗具有巨大的潜力，但仍难以找到一种具有高效药物共载、同步转运和靶向特异性共释放能力的载体，这导致协同作用的效果不理想。为此，本文设计了一种新型壳聚糖两亲体（PEI-ss-HECS-ss-OA，HSPO），它通过聚乙二胺（PEI）和辛胺（OA）分别具有谷胱甘肽（GSH）可逆的阳离子化和疏水性。HSPO 在水溶液中自发组装成胶束系统，并能有效地共包封两种药物，且剂量比可调。通过透明质酸（HA）包覆的表面电荷反转策略，带负电荷（-21.45 ± 1.44 mV）和合适粒径（192.52 ± 7.41 nm）的 HA(HSPO)共递药胶束通过被动和主动靶向机制选择性地聚集在过表达 CD44 的 A549 肿瘤中。然后，通过 GSH 触发两亲组装的崩溃以及正电荷凝聚的减少，实现肿瘤细胞质的选择性共释放，最终导致协同抗肿瘤效果增强，抑制率达到 86.63%。总之，本研究验证了 HSPO 作为一种高效的、具有组织特异性的、快速共转运 siRNA 和化疗药物的载体，具有显著的协同肿瘤抑制作用的巨大潜力。
