Stimuli-responsive Nanoparticles for the Efficient Co-delivery of Chemotherapeutic Agents Doxorubicin and siPD-L1 to enhance the anti-tumor effect
作者单位：苏州大学药学院
会议名称：《2018年第十二届中国药物制剂大会》
会议日期：2018年
学科分类：1006[医学-中西医结合] 10[医学] 100602[医学-中西医结合临床]
关 键 词：PEGylation tumor acidity reduction sensitivity siRNA chemotherapy immunity therapy
摘 要：In this work, we designed dual pH/reduction sensitive nanoparticles, which were composed of polyL-lysine-lipoic acid（PLL-LA） as a reduction-responsive core, and modified with a tumor extracellular pH（pHe） triggered detachable PEG layer（sPEG） for the efficient co-delivery of doxorubicin（DOX） and PD-L1 siRNA（siPD-L1）. Under the physiological condition, the PEG layer was stable and led to prolonged circulation time. After accumulated in tumor sites, pHe-sensitive linkage between PEG layer and NPs degraded, which enhanced the internalization of NPs by tumor cells. Then, the high-concentration glutathione（GSH） within tumor cells triggered the destabilization of DOX-siPD-L1/sPEG-PLL-LA NPs, followed by rapid release of payloads DOX and siPD-L1 which diffused to nuclei and siPD-L1 in cytoplasm, respectively. Compared with that at p H 7.4, s PEG-PLL-LA NPs exhibited a higher cellular uptake and improved cytotoxicity against B16 cells in vitro at pH 6.5. Moreover, the sPEG NPs showed good tumor-targeting ability and excellent tumor-penetrating efficacy in tumor tissues. In conclusion, the sPEG modified NPs provided great potentials in cancer treatment.