Effect of sequential release of sirolimus and rosuvastatin using silk fibroin microneedle to prevent intimal hyperplasia

Abstract

Intimal hyperplasia (IH) is a major cause of vascular restenosis after bypass surgery, which progresses as a series of processes from the acute to chronic stage in response to endothelial damage during bypass grafting. A pharmacological approach is required to understand the key signalling pathways at each stage to prevent IH. A strategic localized drug delivery system that reflects the pathophysiology of IH and minimizes systemic side effects is necessary in addition to systemic therapeutic approaches using oral or intravenous drugs. In this study, the sequential release of sirolimus, a mechanistic target of rapamycin (mTOR) inhibitor, and statin, an HMG-COA inhibitor, was realized as a silk fibroin-based microneedle device in vivo. The released sirolimus in the acute stage reduced vascular smooth muscle cell (VSMC) proliferation and vascular fibrosis through transforming growth factor (TGF)-beta/mTOR inhibition. Furthermore, rosuvastatin, which was continuously released from the acute to chronic stage, reduced vascular stiffness and apoptosis through TGF-beta/Yes-associated protein inactivation. The sequential release of sirolimus and rosuvastatin confirmed the synergistic treatment effects on vascular inflammation, autophagy, VSMC proliferation, and extracellular matrix degradation remodeling through inhibition of the mTOR/nuclear factor kappa B pathway. These results demonstrate the therapeutic effect on preventing restenosis with sufficient vascular elasticity and significantly reduced vascular fiber density of the neointima in response to endothelial damage. We also confirmed the safety of drug toxicity by delivering the drug to the target lesion rather than by systemic diffusion. Thus, the study suggests a promising strategy for treating coronary artery disease in patients with underlying conditions such as diabetes, hypertension, and hyperlipidemia through localized drug delivery of customized drug combinations.