Boosting SN38-based oral chemotherapy to combine reductionbioactivated structured lipid-mimetic prodrug with ascorbic acid  

作　　者：Helin Wang Qi Lu Yifan Miao Jiaxuan Song Mingyang Zhang Zixuan Wang Haotian Zhang Zhonggui He Chutong Tian Jin Sun 

机构地区：[1]Department of Pharmaceutics,Wuya College of Innovation,Shenyang Pharmaceutical University,Shenyang 110016,China [2]School of Life Science and Biopharmaceutics,Shenyang Pharmaceutical University,Shenyang 110016,China

出　　处：《Nano Research》2022年第10期9092-9104,共13页纳米研究（英文版）

基　　金：supported by the National Key Research and Development Program of China(No.2021YFA0909900);the National Natural Science Foundation of China(Nos.82073777,82104109,and 82173766).

摘　　要：The reduction-responsive disulfide bonds have been widely used as bioactive linkages to facilitate a rapid release of anticancer drugs into tumor cells.However,the activation can be hindered by the kinetics of the thiol-disulfide exchange reactions.Supplementing with an additional reductant is a promising strategy to further boost drug release.Herein,inspired by the specific absorption mechanism of triglyceride fat,structured lipid-mimetic oral prodrugs of 7-ethyl-10-hydroxycamptothecin(SN38)were designed to improve intestinal permeability and bypass the first-pass effect.SN38 prodrugs were prepared into lipid formulations that could self-emulsify into nano-sized particles after entering the gastrointestinal tract.Surprisingly,we found that the oral bioavailability of the prodrug lipid formulation could be up to 2.69-fold higher than that of the parent SN38,indicating an effective oral delivery.In addition,the reduction-responsive disulfide bond was used as a linker,and ascorbic acid(ASC)was coadministrated to further promote the efficient release of SN38 from the prodrug.ASC enhanced the oral antitumor effect of the reduction-responsive oral prodrug and exhibited good safety.In summary,the combination of a structured lipid-mimetic prodrug and ASC was firstly demonstrated to boost the oral chemotherapy effect of the difficult-for-oral chemotherapeutics.

关 键 词：oral chemotherapy structured lipid-mimetic prodrug 7-ethyl-10-hydroxycamptothecin(SN38) ascorbic acid 

分 类 号：R730.53[医药卫生—肿瘤]