title: Zwitterionic nanoparticles constructed from bioreducible RAFT-ROP double head agent for shell shedding triggered intracellular drug delivery.
abstract: Nanomedicines have emerged as indispensable platforms for cancer theranostics, however, the therapeutic outcomes were often compromised not only by the multiple biological barriers during the itinerary from the initial injection site to the intracellular action site but also the insufficient drug release at the pathological site. Herein, novel bioreducible double head agent, combining reversible addition-fragmentation chain transfer agent and ring opening polymerization initiator through disulfide linkage, was firstly prepared. Well-defined cRGDfK-polycarboxybetaine methacrylate-SS-polycaprolactone block copolymers (termed as cRGD-PCSSL) were facilely synthesized using this initiator. Subsequently, shell sheddable and drug-encapsulated zwitterionic nanoparticles were constructed by one-step self-assembly with doxorubicin (DOX) (termed as cRGD-PCSSL/DOX NPs). The reduction-responsive shedding of PCB shells resulted in the rapid loss of cRGD-PCSSL/DOX NPs stability in the presence of glutathione, facilitating the rapid DOX release. Results of flow cytometry and fluorescence microscopy demonstrated that cRGD-PCSSL/DOX NPs could be internalized by HepG2 cells via receptor-mediated endocytosis with fast intracellular drug release, leading to considerable cytotoxicity in comparison with free DOX. Importantly, the low protein adsorption and excellent serum stability properties of cRGD-PCSSL/DOX NPs translated into prolonged systemic circulation and enhanced tumor accumulation. Furthermore, intravenous injection of cRGD-PCSSL/DOX NPs in tumor-bearing mice exhibited significantly higher antitumor efficiency and lower systemic toxicity compared to free DOX. Consequently, the novel zwitterionic NPs, which facilely overcome the dilemma between multifunctionality and complexity by programmatically circumventing the multiple biological barriers, would represent a promising platform for enhanced anticancer drug delivery.
  
  
  
  Herein, novel bioreducible RAFT and ROP double-head agent was first reported for the synthesis of cRGDfK-polycarboxybetaine methacrylate-SS-polycaprolactone zwitterionic block copolymers (cRGD-PCB-SS-PCL, termed as cRGD-PCSSL) through controllable polymerization methods. Firstly, this synthetic route surmounted the major disadvantage of most current used methods, which required thiol exchange reaction between active disulfide bond and free thiol groups at the chain ends. Secondly, the prepared cRGD-PCSSL/DOX NPs reasonably integrated cRGD for active tumor targeting and receptor-mediated endocytosis, zwitterionic PCB with nonfouling property for prolonged systemic circulation, disulfide linkage for reduction-responsive drug release, biodegradable PCL for hydrophobic anticancer drug loading. Finally, the systematic evaluation fully verified that the in vitro optimized cRGD-PCSSL/DOX NPs translated into significantly better therapeutic efficiency with reduced side effects in vivo.
authors.affiliation: Department of Polymer Science and Technology and Key Laboratory of Systems Bioengineering of the Ministry of Education, School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, China; Collaborative Innovation Center of Chemical Science and Engineering, Tianjin 300072, China.
authors.forename: Pingsheng
authors.initials: P
authors.lastname: Huang
authors.affiliation: Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Science & Peking Union Medical College, Tianjin 300192, China.
authors.forename: Jinjian
authors.initials: J
authors.lastname: Liu
authors.affiliation: Institute of Biomedical Engineering, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300192, China.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Wang
authors.affiliation: Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Science & Peking Union Medical College, Tianjin 300192, China.
authors.forename: Yumin
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Polymer Science and Technology and Key Laboratory of Systems Bioengineering of the Ministry of Education, School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, China; Collaborative Innovation Center of Chemical Science and Engineering, Tianjin 300072, China.
authors.forename: Fuli
authors.initials: F
authors.lastname: Zhao
authors.affiliation: Institute of Biomedical Engineering, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300192, China.
authors.forename: Deling
authors.initials: D
authors.lastname: Kong
authors.affiliation: Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Science & Peking Union Medical College, Tianjin 300192, China. Electronic address: lewis78@163.com.
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Polymer Science and Technology and Key Laboratory of Systems Bioengineering of the Ministry of Education, School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, China; Collaborative Innovation Center of Chemical Science and Engineering, Tianjin 300072, China. Electronic address: ajdong@tju.edu.cn.
authors.forename: Anjie
authors.initials: A
authors.lastname: Dong
mesh_terms: D000818:Animals; D001622:Betaine / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D004317:Doxorubicin / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D016503:Drug Delivery Systems / Q000379:methods*; D004354:Drug Screening Assays, Antitumor; D005260:Female; D056945:Hep G2 Cells; D006801:Humans; D053758:Nanoparticles / Q000737:chemistry / Q000627:therapeutic use; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D009842:Oligopeptides / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D011091:Polyesters / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D011109:Polymethacrylic Acids / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D000068936:Theranostic Nanomedicine / Q000379:methods
chemical_list: D009842:Oligopeptides; D011091:Polyesters; D011109:Polymethacrylic Acids; C517178:polycarboxybetaine methacrylate; C016240:polycaprolactone; D001622:Betaine; C047981:arginyl-glycyl-aspartic acid; D004317:Doxorubicin
keywords: Doxorubicin; Nanoparticles; Reduction-responsive; Tumor targeting; Zwitterionic