Efficient Treatment of Atherosclerosis by Dexamethasone Acetate and Rapamycin Co-Loaded mPEG-DSPE Calcium Phosphate Nanoparticles

Abstract

Atherosclerosis (AS) is one of the leading causes of vascular disease, producing high morbidity and mortality in many countries. Autophagy plays an important role when cells are facing serious circumstances, such as oxidative stress induced by Ox-LDL (oxidized low-density lipoprotein). Recent studies have revealed that DEX (dexamethasone acetate) and RAPA (rapamycin) exhibit efficient AS therapeutic ability by protecting endothelial cells and killing foam cells, respectively. Herein, we hypothesize that combining DEX and RAPA together in a specific nanocarrier system can achieve better AS therapy while limiting harmful effects. As a proof of concept, DEX and RAPA coloaded mPEG2k-DSPE calcium phosphate (CaP) nanoparticles (DR-NPs) were prepared by using a biomineralization method. DR-NPs increased HUVEC survival and induced foam cell apoptosis in vitro, which were correlated with autophagy activity. DR-NPs efficiently aggregated at AS plaques in the carotid artery and abdominal artery in ApoE– / – mice 24 h after i.v. injection. Moreover, DR-NPs exhibited excellent plaque regression ability, with smaller necrotic cores and lipid core areas observed after in vivo treatment. Furthermore, the function of vascular endothelial cells was largely promoted, as evidenced by the dramatically decreased expression levels of adhesion factors, such as MMP-2, MMP-9 and ICAM-1. Consequently, DR-NPs can act as an effective AS therapeutic agent and broaden the AS therapeutic approach by inducing autophagy.

Identification of Biomarkers of Autophagy-Related Genes Between Early and Advanced Carotid Atherosclerosis

“… 16 DR-NPs (DEX and RAPA-coloaded mPEG2k-DSPE calcium phosphate nanoparticles) efficiently aggregated at atherosclerosis plaques in the abdominal artery in mice and exhibited excellent plaque regression ability by inducing autophagy, with smaller necrotic cores and lipid core areas observed after in vivo treatment. 17 Mechanistically, miR-100 indirectly stimulated endothelial autophagy in vitro and in vivo, and attenuated aortic atherogenesis, resulting in a decrease of plaque area by 45%. 18 The occurrence process of carotid atherosclerosis includes four pathological stages: intimal thickening, intimal xanthoma, thin fiber cap atheroma and thick fiber cap atheroma.…”

cRGD Peptide-Modified Nanocarriers for Targeted Delivery of Angiogenesis Inhibitors to Attenuate Advanced Atherosclerosis

“…In addition, the side effects of PEDF RNPs on kidneys, spleen, liver, lungs, and heart were determined by H&E staining, and liver and kidney function was also assessed. C57 mice of the same age were taken as a negative control …”

Mammalian Target of Rapamycin as the Therapeutic Target of Vascular Proliferative Diseases: Past, Present, and Future

“…Rapamycin inhibits the proliferation of pulmonary vascular cells, including VSMCs and endothelial cells by inhibiting mTORC1 and mTORC2. 88,[118][119][120][121] Notably, preclinical research data have shown that rapamycin treatment, both acute and chronic, has strong antiproliferation effects and can prevent the development of pulmonary vascular remodeling in rats with pulmonary hypertension. 3,88,122 However, clinical studies have shown that both short-term and long-term rapamycin therapy, while having antiproliferative effects and inhibiting the progression of pulmonary vascular remodeling, still fails to induce apoptosis and reverse pulmonary vascular remodeling in patients with IPAH and normal human PASMCs under chronic hypoxic conditions.…”