Fine-tuning the structure-tolerance-antitumor efficacy axis of prodrug nanoassemblies via branched aliphatic functionalization  

作　　者：Guanting Li Fengli Xia Hongying Xiao Shunzhe Zheng Shuwen Fu Han Qiao Qianhui Jin Xuanbo Zhang Dun Zhou Chutong Tian Jin Sun Zhonggui He Bingjun Sun 

机构地区：[1]Department of Pharmaceutics,Wuya College of Innovation,Shenyang Pharmaceutical University,Shenyang 110016,China [2]Department of Pharmaceutics,College of Pharmacy,Shenyang Pharmaceutical University,Shenyang 110016,China [3]Emergency Department,The First Affiliated Hospital of Jinzhou Medical University,Jinzhou 121001,China

出　　处：《Nano Research》2024年第4期2908-2918,共11页纳米研究（英文版）

基　　金：supported by National Natural Science Foundation of China(Nos.82272151,82204318 and 82173766);Doctoral Scientific Research Staring Foundation of Liaoning Province(No.2021-BS-130);General Program of Department of Education of Liaoning Province(No.LJKZ0953);Shenyang Young and Middle-aged Science and Technology Innovation Talent Support Program(No.RC220389).

摘　　要：Small-molecule prodrug nanoassemblies have emerged as efficient antitumor drug delivery systems.However,in the case of camptothecins-based prodrug nanoassemblies,linear aliphatic side chain modification often results in rod-shaped or irregularly shaped nanoassemblies,which are highly unfavorable for sterilization through filtration,and may cause capillary blockage upon intravenous injection.The rational design of camptothecins-based prodrug nanoassemblies remains a challenge.Herein,we propose that branched aliphatic alcohol(BAA)functionalization could fine-tune the structure-tolerance-antitumor efficacy axis of prodrug nanoassemblies.Correspondingly,four SN38-BAA prodrugs were synthesized by conjugating 7-ethyl-10-hydroxycamptothecin(SN38)with BAAs of varying lengths via a tumor redox-responsive disulfide bond,which self-assemble into uniform spherical nanoparticles.The length of BAA was found to significant impact the multiple drug delivery process,including colloidal stability,drug release profiles and pharmacokinetics.Overall,SN38-C21 NPs(SN38-11-heneicosanol nanoparticles),featuring the longest BAA,showcased multiple therapeutic advantages,ultimately culminating the optimal antitumor efficacy and tolerance.The findings underscore the potential of BAA functionalization in strengthening the therapeutic outcomes of prodrug nanoassemblies,and provide valuable insights for developing translational camptothecins-based nanomedicines.

关 键 词：prodrug nanoassembly self-assembly antitumor efficacy TOLERANCE 7-ethyl-10-hydroxycamptothecin(SN_(3)8) 

分 类 号：O62[理学—有机化学]