Lin Wenjing, Yao Na, Li Hongru, Hanson Samuel, Han Wenqing, Wang Chun, Zhang Lijuan
School of Chemistry and Chemical Engineering, South China University of Technology, Guangzhou 510640, China.
Department of Biomedical Engineering, University of Minnesota, Minneapolis, MN 55455, USA.
Polymers (Basel). 2016 Nov 16;8(11):397. doi: 10.3390/polym8110397.
Dual functional unimolecular micelles based on a pH-responsive amphiphilic star polymer β-CD-(PLA--PDMAEMA--PEtOxMA) have been developed for the co-delivery of imiquimod and plasmid DNA to dendritic cells. The star polymer with well-defined triblock arms was synthesized by combining activator regenerated by electron-transfer atom-transfer radical polymerization with ring-opening polymerization. Dissipative particle dynamics simulation showed that core-mesophere-shell-type unimolecular micelles could be formed. Imiquimod-loaded micelles had a drug loading of 1.6 wt % and a larger average size (28 nm) than blank micelles (19 nm). The release of imiquimod in vitro was accelerated at the mildly acidic endolysosomal pH (5.0) in comparison to physiologic pH (7.4). Compared with blank micelles, a higher NP ratio was required for imiquimod-loaded micelles to fully condense DNA into micelleplexes averaging 200⁻400 nm in size. In comparison to blank micelleplexes, imiquimod-loaded micelleplexes of the same N:P ratio displayed similar or slightly higher efficiency of gene transfection in a mouse dendritic cell line (DC2.4) without cytotoxicity. These results suggest that such pH-responsive unimolecular micelles formed by the well-defined amphiphilic star polymer may serve as promising nano-scale carriers for combined delivery of hydrophobic immunostimulatory drugs (such as imiquimod) and plasmid DNA with potential application in gene-based immunotherapy.
基于pH响应性两亲性星形聚合物β-CD-(PLA--PDMAEMA--PEtOxMA)的双功能单分子胶束已被开发用于将咪喹莫特和质粒DNA共递送至树突状细胞。通过将电子转移原子转移自由基聚合再生的活化剂与开环聚合相结合，合成了具有明确三嵌段臂的星形聚合物。耗散粒子动力学模拟表明可以形成核-介观-壳型单分子胶束。负载咪喹莫特的胶束药物负载量为1.6 wt%，平均尺寸（28 nm）比空白胶束（19 nm）大。与生理pH（7.4）相比，在轻度酸性的溶酶体pH（5.0）下，咪喹莫特在体外的释放加速。与空白胶束相比，负载咪喹莫特的胶束需要更高的NP比才能将DNA完全浓缩成平均尺寸为200⁻400 nm的胶束复合物。与空白胶束复合物相比，相同N:P比的负载咪喹莫特的胶束复合物在小鼠树突状细胞系（DC2.4）中显示出相似或略高的基因转染效率，且无细胞毒性。这些结果表明，由明确的两亲性星形聚合物形成的这种pH响应性单分子胶束可能作为有前景的纳米级载体，用于疏水性免疫刺激药物（如咪喹莫特）和质粒DNA的联合递送，在基于基因的免疫治疗中具有潜在应用。
