Transferrin-inspired vehicles based on pH-responsive coordination bond to combat multidrug-resistant breast cancer

Abstract A novel biomimetic drug delivery system (BDDS) inspired by the pH-dependent ferric ion-transport and release manner of transferrin (Tf) was developed for combating multidrug-resistant breast cancer. Tf-inspired carrier was synthesized by modifying bovine serum albumin (BSA) with histamine (HA) through amide reaction to provide superior specific coordination sites for ferric ion-drug complexes, and self-assembled into nanoparticles (NPs) induced by coordination bond. Tf-inspired NPs were prepared via environment-friendly method, and well redispersed in saline after lyophilization. When internalized into tumor cells by SPARC (secreted protein acidic and rich in cysteine) mediated endocytosis, Tf-inspired NPs bypassed and decreased the P-glycoprotein-mediated drug efflux and led to more effective treatment of multidrug-resistant breast cancer compared with free drugs both in vitro and in vivo due to the enhanced cellular uptake and rapid pH-responsive drug release. Moreover, Tf-inspired NPs exhibited good biocompatibility and low systemic toxicity. Thus, our results demonstrate that Tf-inspired NPs based on coordination bond represent as a smart drug delivery strategy to combat multidrug-resistant cancer and have great potential for clinical applications in cancer therapy.