Multiple pH responsive zwitterionic micelles for stealth delivery of anticancer drugs

Abstract

In this work, we reported zwitterion-functionalized “stealth” micelles for intelligent delivery of anticancer drugs. The amphiphilic polymer, poly(carboxybetaine methacrylate)-block-poly[2,2-di(acryloyloxy-1-ethoxy)propane-co-4,4-trimethylene dipiperidine [pCBMA-b-p(ADA-TMDP)], was synthesized via ATRP and subsequent Michael addition reaction. The assembled polymeric micelles were demonstrated as nanoscale (69 ± 20 nm) carriers possessing zwitterionic tentacles. Specifically, the hydrophilic zwitterionic tentacles, which were composed of the pCBMA component, could not only significantly resist protein adsorption to realize “stealth” transportation and prolong the circulation time of the drug delivery system in the blood stream, but also reverse its surface charge to facilitate cellular uptake in response to the extracellular pH environment (pH 6.8); the steady drug encapsulation cavities, as assemblies of p(ADA-TMDP) units, endowed the micelles intracellular environmental pH-responsive properties for potential endosomal escape and desired drug release after their accumulation in tumor sites through the EPR effect. The anticancer activity of these zwitterionic micelles carrying doxorubicin (DOX) was systematically studied here. At low pH (e.g., pH 5.0), cleavage of the ketal bonds of the ADA segments and protonation of the TMDP segments both contributed to the swelling and disassembly of the zwitterionic micelles. Moreover, protonation of TMDP segments caused water influx and thus facilitated micelle endosomal escape. The drug release profiles revealed that these zwitterionic micelles could accelerate drug release remarkably more (3.26-fold) at pH 5 than pH 7.4, indicating the great potential to quickly release the vast majority of the drug in tumor tissue. Both in vitro and in vivo evaluations verified the high anticancer efficiency and greatly reduced side effects of DOX-loaded zwitterionic micelles as compared with the free drug DOX·HCl.