PEGylated Polyethylenimine Derivative-Mediated Local Delivery of the shSmad3 Inhibits Intimal Thickening after Vascular Injury

Abstract

Intimal hyperplasia is a complex process which contributes to several clinical problems such as atherosclerosis and postangioplasty restenosis. Inhibition of Smad3 expression inhibits intimal thickening. Our previous study has modified biscarbamate cross-linked polyethylenimine derivative (PEI-Et) through PEGylation thus obtained polyethylene glycol-graft-polyethylenimine derivative (PEG-Et 1:1), which has lower cytotoxicity and higher gene transfection efficiency compared with PEI-Et. In this study, PEG-Et 1:1 was employed in Smad3 shRNA (shSmad3) delivery for preventing intimal hyperplasia after vascular injury. It was observed that PEG-Et 1:1 could condense shSmad3 gene into nanoparticles with particle size of 115–168 nm and zeta potential of 3–6 mV. PEG-Et 1:1 displayed remarkably lower cytotoxicity, higher transfection efficiency, and shRNA silencing efficiency than PEI-Et and PEI 25 kDa in vascular smooth muscle cells (VSMCs). Moreover, PEG-Et 1:1/shSmad3 polyplex treatment significantly inhibited collagen, matrix metalloproteinase 1 (MMP1), MMP2 and MMP9 expression, and upregulated tissue inhibitor of metalloproteinase 1 (TIMP1) expression both in vitro and in vivo. Furthermore, intravascular delivery of shSmad3 with PEG-Et 1:1 polyplex efficiently reduced Smad3 expression and inhibited intimal thickening 14 days after vascular injury. Ultimately, this study indicated that PEG-Et 1:1-mediated local delivery of shSmad3 is a promising strategy for preventing intimal thickening.

<p>Honokiol-mesoporous Silica Nanoparticles Inhibit Vascular Restenosis via the Suppression of TGF-β Signaling Pathway</p>

“…Wei et al β pathway through different means can decrease intimal hyperplasia. 34,[36][37][38] To evaluate the potential inhibitory effects on TGF-β signaling pathway, Western blots were performed on p-smad3 of VSMCs treated with free-honokiol, MSNPs and HNK-M. As shown in Figure 5A and B, overexpression of p-smad3 on VSMCs was observed by irritation with TGFβ (5 ng/mL) for one hour. The phosphorylation state of smad3 can be inhibited by free-honokiol and HNK-M, and the inhibitory effects of HNK-M is more obvious than that of free-HNK.…”