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Zwitterionic shielded polymeric prodrug with folate-targeting and pH responsiveness for drug delivery.

Zwitterionic polymers are a class of polymers that acts as both Lewis base and Lewis acid in solution. These polymers not only have excellent properties of hydration, anti-bacterial adhesion, charge reversal and easy chemical modification, but also have characteristics of long-term circulation and suppress nonspecific protein adsorption in vivo. Here, we describe a novel folate-targeted and acid-labile polymeric prodrug under the microenvironment of tumor cells, abbreviated as FA-P(MPC-co-PEGMA-BZ)-g-DOX, which was synthesized via a combination of reversible addition-fragmentation chain transfer (RAFT) copolymerization, Schiff-base reaction, Click chemistry, and a reaction between the amine group of doxorubicin (DOX) and aldehyde functionalities of P(MPC-co-PEGMA-BZ) pendants, wherein MPC and PEGMA-BZ represent 2-(methacryloyloxy)ethyl phosphorylcholine and polyethylene glycol methacrylate ester benzaldehyde, respectively. The polymeric prodrug could self-assemble into nanoparticles in an aqueous solution. The average particle size and morphologies of the prodrug nanoparticles were observed by dynamic light scattering (DLS) and transmission electron microscopy (TEM), respectively. We also investigated the in vitro drug release behavior and observed rapid prodrug nanoparticle dissociation and drug release under a mildly acidic microenvironment. The methyl thiazolyl tetrazolium (MTT) assay verified that the P(MPC-co-PEGMA-BZ) copolymer possessed good biocompatibility and the FA-P(MPC-co-PEGMA-BZ)-g-DOX prodrug nanoparticles showed higher cellular uptake than those prodrug nanoparticles without the FA moiety. The results of cytotoxicity and the intracellular uptake of non-folate/folate targeted prodrug nanoparticles further confirmed that FA-P(MPC-co-PEGMA-BZ)-g-DOX could be efficiently accumulated and rapidly internalized by HeLa cells due to the strong interaction between multivalent phosphorylcholine (PC) groups and cell membranes. This kind of multifunctional FA-P(MPC-co-PEGMA-BZ)-g-DOX prodrug nanoparticle with combined target-ability and pH responsiveness demonstrates promising potential for cancer chemotherapy.