Dual-targeting nanoparticles with core-crosslinked and pH/redox-bioresponsive properties for enhanced intracellular drug delivery.

Abstract

Multifunctional nanoparticles (NPs) with high blood-stability, tumor-targeting ability, and stimuli-bioresponsive drug release behaviors are urgently demanded. Herein, folic acid (FA) and galactose (GAL) functionalized, core-crosslinked NPs (CC NPs) with dual-targeting and pH/redox-bioresponsive properties were developed based on amphiphilic FA-poly(6-O-methacryloyl-d-galactopyranose)-b-poly[2-(diisopropylamino) ethyl methacrylate-co-pyridyl disulfide methylacrylate] [FA-PMAgGP-b-P(DPA-co-PDEMA), termed as FA-PMgDP] block copolymers, and then investigated for facilitated hepatoma-targeting delivery of doxorubicin (DOX). A series of PMgDP copolymers were synthesized though two-step RAFT copolymerization followed by acid-induced acetal deprotection reaction. Their well-defined chemical structures and compositions were characterized by 1H NMR and gel permeation chromatography. Nano-sized, non-crosslinked PMgDP NPs (PMgDP NC NPs) with sizes of less than 25 nm in aqueous solution were self-assembled via the solvent exchange method, and PMgDP CC NPs were readily prepared in the presence of dithiothreitol. The drug-loading content of PMgDP CC NPs was up to 15.8% and its entrapment efficiency was 89.0%. In normal physiological conditions, 11.6% of DOX was released from DOX-loaded PMgDP CC NPs at 25 h, whereas in analogous intracellular microenvironment, 95.5% was released at 11 h owing to the acid-induced protonation of tertiary amine and reductive cleavage of disulfide bond in the hydrophobic core. In a cellular uptake study, FA and GAL-mediated, active, dual-targeted DOX-loaded FA-PMgDP CC NPs showed a 3.54-fold increase in cellular uptake efficiency to HepG2 cells compared to that of shown by single GAL-targeted, DOX-loaded PMgDP NC NPs. Results of in vitro cytotoxicity study showed that blank FA-PMgDP CC NPs exhibited good biocompatibility, whereas dual-targeting DOX-loaded FA-PMgDP CC NPs increased cell apoptosis. Therefore, the above results indicated that the well-constructed FA-PMgDP CC NPs with multi-synergistic effect may serve as new nanocarriers in the field of precise hepatoma-targeting drug delivery.

• Authors: Junqiang Zhao, Caixia Yan, Ze Chen, Jinjian Liu, Huijuan Song, Weiwei Wang, Jianfeng Liu, Ning Yang, Yiping Zhao, Li Chen
• Journal: Journal of colloid and interface science (J Colloid Interface Sci) Vol. 540 Pg. 66-77 (Mar 22 2019) ISSN: 1095-7103 [Electronic] United States
• PMID: 30634060 (Publication Type: Journal Article)
• Copyright: Copyright © 2019 Elsevier Inc. All rights reserved.

Chemical References

• Antibiotics, Antineoplastic
• Delayed-Action Preparations
• Polymers
• Doxorubicin
• Folic Acid
• Galactose

Topics

• Antibiotics, Antineoplastic (administration & dosage, pharmacokinetics, pharmacology)
• Apoptosis (drug effects)
• Delayed-Action Preparations (chemistry)
• Doxorubicin (administration & dosage, pharmacokinetics, pharmacology)
• Drug Delivery Systems
• Drug Liberation
• Folic Acid (analogs & derivatives)
• Galactose (analogs & derivatives)
• Hep G2 Cells
• Humans
• Hydrogen-Ion Concentration
• Nanoparticles (chemistry)
• Neoplasms (drug therapy)
• Oxidation-Reduction
• Polymers (chemistry)