pH-sensitive poly(histidine)-PEG/DSPE-PEG co-polymer micelles for cytosolic drug delivery.

To introduce pH sensitivity into the DSPE-PEG-based micellar system and achieve the quick intracellular drug release in response to the acidity in endosomes, a mixed polymeric micelle was developed based on three grafted copolymers, including 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-polyethylene glycol-2000(DSPE-PEG(2000)), antinucleosome antibody (mAb 2C5)-modified DSPE-PEG(3400) (DSPE-PEG(3400)-2C5), and poly(ethylene glycol)-coupled poly(L-histidine) (PHIS-PEG(2000)). The structure of PHIS-PEG(2000) was confirmed by (1)H NMR spectroscopy. The mixed micelles with the diameter ranging from 110 to 135 nm were prepared using a dialysis method against pH 7.6 PBS. Paclitaxel (PCT) was used as a model drug, the encapsulation efficiency and loading content of PCT were 88% and 5%, respectively. The mixed micelles composed with 50 wt% of PHIS-PEG(2000) showed the desired pH-dependent drug release property with much faster drug release than micelles without PHIS-PEG(2000). At pH around 5.5, about 75-95% of the loaded drug was released within 2 h. The MTT assay showed PCT-loaded mixed micelles had higher cytotoxicity at pH 5.8 than that at pH 7.4. Further modification of the mixed micelles with anti-cancer nucleosome-specific monoclonal antibody 2C5 significantly increased their cellular uptake efficiency and cytotoxicity. Thus, the low pH in endosomes could trigger the PCT release from the pH-sensitive mixed micelles after 2C5-mediated endocytosis. The results of this study suggest that the mixed micelles (DSPE-PEG(2000)/DSPE-PEG(3400)-2C5/PHIS-PEG(2000)) could enhance the tumor cell-specific internalization and trigger the quick drug release, resulting in the improved anti-cancer efficacy.