A G2/M-phase specific drug delivery system based on increased exposure of phosphatidylethanolamine on mitotic cancer cells and low pH in tumor tissues

Abstract

It is a challenge to carry G2/M-phase specific antitumor drugs into G2/M phase of cancer cells. For this purpose, we set up a pH-sensitive mixed micellar system based on poly(ethylene glycol)-b-poly(l-histidine) (PEG-PHIS) and poly(ethylene glycol)-b-poly(D, l-lactide) (PEG-PDLLA), and we used duramycin, a highly specific phosphatidylethanolamine-binding peptide, as a G2/M-phase specific targeting ligand to modify PEG-PDLLA. The mixed micelles were characterized by dynamic light scattering, electron microscopy and the pyrene fluorescence probe method. The G2/M-phase specific anti-cancer drug paclitaxel was loaded with a size of 189 ± 5 nm. And the drug-loading content and encapsulation efficiency were 14.7 ± 0.3% and 89.1 ± 2.5%, respectively. In addition, cytotoxicity assay showed that paclitaxel-loaded mixed micelles had effective antitumor effects, and the blank mixed micelles were safe. Importantly, the micelles showed pH sensitivity and G2/M-phase specific uptake. What's more, pharmacokinetic and in vivo imaging study showed that the mixed micelles displayed a prolonged circulation time and improved targeted accumulation at tumor sites. All these results suggest that the mixed micelle was a promising G2/M-phase specific drug delivery system.