Transferrin receptor-targeted pH-sensitive micellar system for diminution of drug resistance and targetable delivery in multidrug-resistant breast cancer

The emergence of drug resistance is partially associated with overproduction of transferrin receptor (TfR). To overcome multidrug resistance (MDR) and achieve tumor target delivery, we designed a novel biodegradable pH-sensitive micellar system modified with HAIYPRH, a TfR ligand (7pep). First, the polymers poly(L-histidine)-coupled polyethylene glycol-2000 (PHIS-PEG(2000)) and 7pep-modified 1,2-distearoyl-sn-glycero-3-phosphoetha-nolamine-polyethylene glycol-2000 (7pep-DSPE-PEG(2000)) were synthesized, and the mixed micelles were prepared by blending of PHIS-PEG(2000) and 1,2-distearoyl-sn-glycero-3-phos-phoethanolamine-polyethylene glycol-2000 (DSPE-PEG(2000)) or 7pep-DSPE-PEG(2000) (7-pep HD micelles). The micelles exhibited good size uniformity, high encapsulation efficiency, and a low critical micelle concentration. By changing the polymer ratio in the micellar formulation, the pH response range was specially tailored to pH similar to 6.0. When loaded with antitumor drug doxorubicin (DOX), the micelle showed an acid pH-triggering drug release profile. The cellular uptake and cytotoxicity study demonstrated that 7-pep HD micelles could significantly enhance the intracellular level and antitumor efficacy of DOX in multidrug-resistant cells (MCF-7/Adr), which attributed to the synergistic effect of poly(L-histidine)-triggered endolysosom escape and TfR-mediated endocytosis. Most importantly, the in vivo imaging study confirmed the targetability of 7-pep HD micelles to MDR tumor. These findings indicated that 7-pep HD micelles would be a promising drug delivery system in the treatment of drug-resistant tumors.