Multi-stimuli-responsive biohybrid nanoparticles with cross-linked albumin coronae self-assembled by a polymer-protein biodynamer

Wang, L (Wang, Lin)^[ 1 ] ; Liu, L (Liu, Li)^[ 1 ] ; Dong, BY (Dong, Bingyang)^[ 1 ] ; Zhao, HY (Zhao, Hanying)^[ 1 ] ; Zhang, MM (Zhang, Mingming)^[ 2,3 ] ; Chen, WJ (Chen, Wenjuan)^[ 2,3 ] ; Hong, YH (Hong, Yanhang)^[ 2,3 ]

ACTA BIOMATERIALIA, 2017, 54: 259-270

DOI: 10.1016/j.actbio.2017.03.009

 WOS:000402342400022

Abstract

A thermoresponsive polymer-protein biodynamer was prepared via the bioconjugation of an aliphatic aldehyde-functionalized copolymer to hydrazine-modified bovine serum albumin (BSA) through reversible pyridyihydrazone linkages. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and size exclusion chromatography (SEC) results indicated that the pyridyihydrazone linkages cleaved in an intracellular-mimicking acidic milieu, thus leading to the release of BSA. The dynamic character of the protein biodynamer was demonstrated by exchange reactions with aldehyde-containing molecules. The biodynamer self-assembled into spherical micelles at a temperature above its lower critical solution temperature (LCST). Subsequently, BSA molecules within the hydrophilic coronae of the micelles were readily cross-linked via reaction with cystamine at 45 degrees C, and multi-stimuli-responsive nanoparticles were generated. The biohybrid nanoparticles reversibly swelled and shrank as the cores of the nanoparticles were solvated below the LCST and desolvated above the LCST. The accessible reversibility of the pyridylhydrazone bonds imparts pH-responsive and dynamic characteristics to the nanoparticles. The nanoparticles displayed glutathione (GSH) responsiveness, and the synergistic effects of pH and GSH resulted in complete disintegration of the nanoparticles under the intracellular-mimicking acidic and reductive conditions. The nanoparticles were also enzyme-responsive and disintegrated rapidly in the presence of protease. In vitro cytotoxicity and cell uptake assays demonstrated that the nanoparticles were highly biocompatible and effectively internalized by HepG2 cells, which make them interesting candidates as vehicles for drug delivery application and biomimetic platforms to investigate the biological process in nature.