Zwitterionic nanoparticles constructed from bioreducible RAFT-ROP double head agent for shell shedding triggered intracellular drug delivery

摘要

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 giutathione, 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.