title: pH-sensitive poly(histidine)-PEG/DSPE-PEG co-polymer micelles for cytosolic drug delivery.
abstract: 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.
authors.affiliation: Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, Boston, MA 02115, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Wu
authors.forename: Lin
authors.initials: L
authors.lastname: Zhu
authors.forename: Vladimir P
authors.initials: VP
authors.lastname: Torchilin
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D003600:Cytosol / Q000378:metabolism; D004058:Diffusion; D006863:Hydrogen-Ion Concentration; D051379:Mice; D008823:Micelles; D053769:Nanocapsules / Q000008:administration & dosage* / Q000737:chemistry*; D017239:Paclitaxel / Q000008:administration & dosage* / Q000737:chemistry* / Q000493:pharmacokinetics; D010714:Phosphatidylethanolamines / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000737:chemistry*; D011506:Proteins / Q000737:chemistry*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D008823:Micelles; D053769:Nanocapsules; D010714:Phosphatidylethanolamines; D011506:Proteins; C480317:polyhistidine-block-polyethylene glycol; C038089:1,2-distearoylphosphatidylethanolamine; D011092:Polyethylene Glycols; D017239:Paclitaxel