The Application of Targeted Nanodrugs with Dual Responsiveness of PH and Ros in Preventing and Treating Vascular Restenosis

In order to study the application of PH- and Ros-responsive targeted nanodrugs in preventing and treating vascular restenosis, a method based on pH-responsive and reactive oxygen species- (ROS-) responsive carrier materials synthesized in the early stage and rapamycin as a model drug was proposed. This method evaluated the therapeutic advantages of PH and Ros dual-responsive nanoparticles and the effect of dual-responsive active targeted drug delivery nanoparticles on vascular restenosis in vivo by comparing with nonresponsive PH or Ros single responsive nanotherapy. By optimizing the feed mass ratio of pH-responsive materials (ACD) and ROS-responsive materials (OCD), the best pH and ROS responsive nanoparticles were prepared. It has been proved that nanoparticles have ultrasmall volume (10–1000 nm) and can easily pass through the blood vessel wall without causing damage and have the characteristics of targeting and sustained release, so they are an ideal carrier for local administration. Nanoparticles as gene vectors have also achieved good results.

Protective effects of dapagliflozin on vascular remodeling in the carotid artery following balloon injury – potential role of angiotensin and purinergic signaling

Introduction Sodium-glucose co-transporter 2 (SGLT2) inhibitors have been shown to reduce the risk of cardiovascular events independently of glycemic control. The possibility that SGLT2 inhibitors improve endothelial regeneration and vascular restenosis is unknown. Purpose To examine whether dapagliflozin, a selective SGLT2 inhibitor, could prevent neointima thickening induced by balloon injury and, if so, to determine the underlying mechanisms. The effect of dapagliflozin was compared to that of losartan, an angiotensin type 1 receptor (AT1R) antagonist. Methods Saline, dapagliflozin (1.5 mg/kg/day), or losartan (30 mg/kg/day) were administered orally for 5 weeks to male Wistar rats. Balloon injury of the left carotid artery was performed 1 week after starting the treatment and sacrificed 4 weeks later. Vascular reactivity was assessed on left (injured) and right (healthy) carotid artery rings. The extent of neointima was assessed by histomorphometric analysis, changes of target factors by immunofluorescence, RT-qPCR and histochemistry. Results Dapagliflozin and losartan treatments reduced neointima thickening by 32% and 27%, respectively. Blunted contractile responses to phenylephrine and relaxations to acetylcholine and down-regulation of eNOS were observed in the injured artery. These effects were not modified by the dapagliflozin or the losartan treatments. RT-qPCR investigations indicated an increased in gene expression of inflammatory (IL-1beta, ITGAM, VCAM-1), oxidative (p47phox, p22phox) and fibrotic (TGF-beta1) markers and a decreased of eNOS in the injured carotid. However, these changes were not affected by the pharmacological treatments. By contrast, significant increased levels of AT1R angiotensin receptor and NTPDase1 (CD39) ectonucleotidase were observed in the restenotic carotid artery of the dapagliflozin group. Histochemical analysis evidenced important NTPDase1 activity in the neointima. Conclusions Dapagliflozin effectively reduced neointimal thickening. As the contribution of AT1R and P2Y2 ATP receptor in smooth muscle cell proliferation and neointima formation has been reported in the literature, the present data suggest that dapagliflozin prevents restenosis through interfering with angiotensin and/or extracellular nucleotides signaling. SGLT2 transporter represent potential new target for limiting vascular restenosis. FUNDunding Acknowledgement Type of funding sources: Private company. Main funding source(s): This work was supported by AstraZeneca

Preparation of Double-Layer Nanoparticles for Inhibitory Efficiency in Vascular Restenosis via Balloon Infusion

ABSTRACTThe effect of double-layer nanoparticles (DNPs) on vascular restenosis was investigated in this study, which were prepared by combining vascular endothelial growth factor (VEGF) and paclitaxel (PTX). Different blank NPs (Blank), VEGF NPs, PTX-NPs single-layer NPs (PTX-NPs), and DNPs were prepared with VEGF, PTX, polylactic-polyglycolic acid (PLGA), and polyvinyl alcohol (PVA), so as to analyze the cytotoxicity of NPs. Besides, different NPs were compared in terms of the characterization, encapsulation efficiency (EE), in vitro release (IVR), and cell proliferation inhibition ability. 30 adult New Zealand white rabbits were selected to construct a balloon injury model (BIM). Then, they were divided into 5 groups according to different treatment NPs, including a model group (BIM), a Blank group (BIM + Blank NPs); a PTX-NP group (BIM + PTX-NPs), a VEGF-NPs group (BIM + VEGF-NPs), and DNPs group (BIM + DNPs), with 6 rabbits in each group. There was a comparison on the histology, arterial stenosis, hyperplasia index (HI), and intimal thickness (IT) of arterial vessels from different groups, and immunohistochemistry was employed to analyze the changes of VEGF and C-reactive protein (CRP) protein expression levels in arterial tissues of different groups. The results showed that the cell survival rate (SR) was 88.69 ±3.17% and 90.64 ± 1.86% in turn when PLGA and PVA were both 100 ¿tg/mL. The polydispersity index (PDI), minimal Zeta potential (ZP), and average particle size (APS) of DNPs were 0.16 ±0.02, -8.45 ±0.07, and 242.26 ±2.58 nm, respectively. The drug loading (DL) of PTX and plasmid VEGF 165 in DNPs were 29.33% and 4.93%, respectively. The release of PTX from DNPs on the 30th day was close to 50%, and the cumulative release of deoxyribonucleic acid (DNA) was close to 75%. There was no obvious difference in the cell SR within 7 days after DNPs were added into Chinese Hamster ovary (CHO) cells and vascular smooth muscle cells (VSMC) compared with the control group (P > 0.05). The arterial stenosis, HI, and IT of the DNPs group were greatly lower than those of the model group (P < 0.05). The expression of VEGF protein in arterial tissues of DNPs group was higher in contrast to the model group (P < 0.01), while the expression of CRP protein was lower than that of the model group (P < 0.05). It showed that the DNPs combined with VEGF and paclitaxel administered by balloon infusion could obviously inhibit the vascular restenosis by increasing the expression of VEGF and reducing the expression of CRP, which provided a reference for the clinical prevention and treatment of postoperative vascular restenosis.

Honokiol-Mesoporous Silica Nanoparticles Inhibit Vascular Restenosis via the Suppression of TGF-β Signaling PathwayHonokiol-Mesoporous Silica Nanoparticles Inhibit Vascular Restenosis via the Suppression of TGF-β Signaling Pathway

Background and aims: MSNPs improves the solubility of drugs through physical, chemical and other interactions, and can be used to overcome the defects of poor water-solubility of drugs. We used MSNPs standard substance to encapsulate honokiol and then assemble into honokiol-mesoporous silica nanoparticles, and we investigated the effect of these nanoparticles on the process of restenosis after common carotid artery injury in rats.Results: Here, we report a promising delivery system that load honokiol into mesoporous silica nanoparticles (MSNPs), and finally assemble into a nano composite particle. This HNK-MSNPs not merely inhibit proliferation and migration of VSMCs by reducing phosphorylation of Smad3 but also showed a higher suppression of vascular restenosis than the free-honokiol form in a rat model of balloon injury. Conclusions: This drug delivery system supplies a potent nano-platform for the intracellular delivery of honokiol to VSMCs and shows a promising use for the future clinical trial.