Dual redox/pH-responsive hybrid polymer-lipid composites: Synthesis, preparation, characterization and application in drug delivery with enhanced therapeutic efficacy

Abstract

The development of intelligent drug delivery system that can efficiently deliver drug to targeted site and release the cargo in a controlled manner is of great significance for cancer chemotherapy. In the present study, dual redox/pH-sensitive amphiphilic copolymer, cholesterol modified poly (β-amino esters)-grafted disulfide poly (ethylene glycol) methyl ether (PAE(-ss-mPEG)-g-Chol), is successfully synthesized via Michael-type step polymerization using disulfide linkage-containing PEG segment. PEGylated lipid is introduced to fabricate the doxorubicin (DOX)-loaded hybrid polymer-lipid nanoparticles (NPs) with (DOX-HDPLNPs) or without (DOX-HPLNPs) disulfides to receive stable NPs with enhanced loading capacity and improved cellular uptake ability as well as serum stability. The HDPLNPs show not only pH-sensitivity because of poly(β-amino esters) (PAE) residues in main chain but also the redox-responsivity due to the disulfides on the side chains with PEG segments. As expected, the DOX-HDPLNPs exhibited the extended blood circulation time and higher serum stability in normal physiological environment, but once deposited in the tumor microenvironment (e.g. low pH value and high GSH concentration), they underwent a dramatic size transition and charge reversal. These features not only can facilitate the NPs accumulation through the enhanced permeability and retention (EPR) effect and endocytosis by tumor cells but also realize the drug controlled release and more efficient tumor inhibition. The in vitro and in vivo results demonstrate that the DOX-HDPLNPs possess the highest therapeutic efficacy with high cellular uptake and negligible cytotoxicity compared to the controls and free drug. Therefore, the HDPLNPs have good potential as smart delivery platforms for hydrophobic anticancer drug delivery due to high uptake by tumor cells and redox/pH-triggered drug release.