Journal
ACS APPLIED MATERIALS & INTERFACES
Volume 11, Issue 51, Pages 47785-47797Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsami.9b18144
Keywords
gene delivery system; H2O2-responsive; shielding system; enhanced endocytosis; H2O2 consumption; cell apoptosis; cancer therapy
Funding
- National Natural Science Foundation of China [51925305, 51520105004, 51873208, 51833010, 51803210, 51973217]
- National Science and Technology Major Projects for Major New Drugs Innovation and Development [2018ZX09711003-012]
- National Program for Support of Top-notch Young Professionals
- Jilin Province Science and Technology Development Program [20180414027GH]
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Constructing an efficient in vivo gene delivery system has always been extremely challenging. Herein, a highly efficient H2O2-responsive in vivo polycationic gene delivery system is developed for the first time. The efficient vector PLL-RT (i.e., polylysine grafted with p-tosyl-L-arginine) is used to mediate plasmid DNA (pDNA) delivery, and H2O2-responsive thioketal dipropanedioic acid-modified dextran (TDPAD) is used as a shielding system for effectively coating vector/pDNA polyplexes. The constructed gene delivery system exhibits a prolonged circulatory half-life in vivo and accelerates the accumulation of vector/DNA polyplexes in tumor tissue by the enhanced permeability and retention (EPR) effect. Moreover, this gene delivery system exhibits highly efficient and synergistic antitumor effects through a strategy of killing three birds with one stone. First, upon the arrival of TDPAD/PLL-RT/pDNA [abbreviated as T(PD)] at the tumor site by the EPR effect, TDPAD reacts with excess H2O2 in tumor tissue, contributing to the detachment of TDPAD, and PLL-RT then mediates the enhanced endocytosis of pDNA encoding shVEGF and significantly downregulates the expression of vascular endothelial growth factor (VEGF) in tumor tissue, exhibiting an outstanding antitumor effect. Second, the H2O2 consumption by TDPAD significantly decreases the H2O2 level in tumor tissue, which synergistically suppresses tumor growth. Third, small-molecule product mercaptopropionic acid, generated by the reaction of TDPAD with H2O2, can induce cancer cell apoptosis and exert pronounced antitumor efficacy. This polycationic gene delivery system shows negligible toxicity in vitro and in vivo. This strategy provides an ideal platform for constructing an efficient in vivo gene delivery system and has bright prospects for cancer therapy.
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