Carrier‐free Janus nano‐prodrug based on camptothecin and gemcitabine: Reduction‐triggered drug release and synergistic in vitro antiproliferative effect in multiple cancer cells
Carrier‐free Janus nano‐prodrug based on camptothecin and gemcitabine: Reduction‐triggered drug release and synergistic in vitro antiproliferative effect in multiple cancer cells
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DOI：
10.1016/j.ijpharm.2018.08.041
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发表时间：
2018-10
影响因子：
5.8
通讯作者：
Yanyun Xu;Yushu Huang;Xiongwen Zhang;Wei Lu;Jiahui Yu;ShiYuan Liu
中科院分区：
文献类型：
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作者：
Yanyun Xu;Yushu Huang;Xiongwen Zhang;Wei Lu;Jiahui Yu;ShiYuan Liu
以氧化还原敏感的二硫键连接吉西他滨和喜树碱，制备了一种无载体、可还原降解的Janus前药CPT-SS-GEM。该两亲性前药具有较高的载药量，分别为CPT的42.6%和GEM的32.2%。利用CPT-SS-GEM前药的两亲性，在水溶液中，CPT-SS-GEM前药可以自组装成Janus纳米前药，不需要任何赋形剂。通过透射电镜观察证实了纳米前药的形态为球形颗粒。纳米前药的快速释药呈还原依赖性，在模拟肿瘤细胞的微环境中（pH6.5PBS，含2 mMDTT），3 h内释药率达90%以上。CPT和GEM的同时释放和成比例释放使得Janus纳米前药CPT-SS-GEM在多种癌细胞株（包括A549、NCI-H460、HCT 116、HT-29和MCF-7/ADR）中具有显著的体外协同抗增殖作用，当癌细胞增殖抑制率超过50%时。联合指数分别为1.04-0.4（A549）、0.24-0.60（NCI-H460）、0.42-0.16（HCT 116）、1.98-0.15（HT-29）、0.36-0.19（MCF-7/ADR）。总之，无载体、氧化还原敏感的Janus纳米前药CPT-SS-GEM是作为化疗药物的协同组合的有希望的候选物。
A carrier-free and reduction-degradable Janus prodrug, termed as CPT-SS-GEM, was fabricated by redox-sensitive disulfide bond linked gemcitabine and camptothecin. This amphiphilic prodrug showed high drug loading capacity, 42.6% of CPT and 32.2% of GEM, respectively. Benefiting from its amphiphilic property, CPT-SS-GEM prodrug could self-assemble into Janus nano-prodrug in water without aid of any excipient. The morphology of the nano-prodrug was spherical particle confirmed by TEM. The rapid drug release from the nano-prodrug proceeded in a reduction-dependent manner, more than 90% of the native CPT and GEM were released in the mimic microenvironment of tumor cells (pH 6.5 PBS containing 2 mM DTT) within a period of 3 h. The concurrent and ratio-metric release of CPT and GEM endowed the Janus nano-prodrug CPT-SS-GEM with pronouncedin vitrosynergistic antiproliferative effect in multiple cancer cell lines when the inhibition rate of cancer cell proliferation exceeded 50%, including A549, NCI-H460, HCT116, HT-29, and MCF-7/ADR. The combination index values showed as followings, 1.04–0.4 (A549), 0.24–0.60 (NCI-H460), 0.42–0.16 (HCT116), 1.98–0.15 (HT-29), 0.36–0.19 (MCF-7/ADR). Taken together, the carrier-free, redox-sensitive Janus nano-prodrug CPT-SS-GEM is a promising candidate as synergistic combination of chemotherapeutics.