Adventitial delivery of miR-145 to treat intimal hyperplasia post vascular injuries through injectable and in-situ self-assembling peptide hydrogels.

Intimal hyperplasia is a common lesion that can be observed in diverse vascular diseases. Drug-eluting stents and drug-coated balloons, which can release anti-proliferative agents to inhibit smooth muscle cell (SMC) proliferation, are developed to prevent intimal hyperplasia. However, these intervention devices still cannot achieve satisfactory clinical outcomes. In contrast to endovascular drug delivery, vascular adventitial drug delivery is a new strategy. To develop a vascular adventitial drug delivery system to treat intimal hyperplasia post vascular injuries, we loaded miR-145-5p-agomir (miR-145) into an injectable and in-situ self-assembling RAD peptide hydrogel. In vitro data showed that the miR-145 could be well incorporated into the RAD peptide hydrogels and released in a slow and controlled manner. The released miR-145 could transfect SMCs successfully, and the transfected SMCs exhibited a reduced migration capacity and higher expressions of SMC contractile biomarkers as compared to the non-transfected SMCs. In vivo data showed that the retention of the miR-145 was greatly elongated by the RAD peptide hydrogels. In addition, the application of the miR-145-loaded RAD peptide hydrogels surrounding injured arteries decreased the proliferative SMCs, promoted the regeneration of endothelium, reduced the macrophage infiltration, inhibited the neointimal formation and prevented adverse ECM remodeling via downregulation of KLF4 expression. The RAD peptide hydrogels loaded with miR-145 can successfully inhibit intimal hyperplasia after vascular injuries and thus hold great potential as an innovative extravascular drug delivery approach to treat vascular diseases. STATEMENT OF SIGNIFICANCE: Intimal hyperplasia is a common lesion that can be observed in diverse vascular diseases. Drug-eluting stents and drug-coated balloons, which can release anti-proliferative agents to inhibit smooth muscle cell (SMC) proliferation, are developed to prevent intimal hyperplasia. However, these intervention devices still cannot achieve satisfactory clinical outcomes. In contrast to endovascular drug delivery, vascular adventitial drug delivery is a new strategy. Our work here demonstrates that the RAD peptide hydrogels loaded with miR-145-5p-agomir (miR-145) can successfully reverse intimal hyperplasia after vascular injuries and thus hold great potential as an innovative vascular adventitial drug delivery approach to treat vascular diseases. Our work proposes a possible paradigm shift from endovascular drug delivery to extravascular drug delivery for vascular disorder treatment.

Current developments in endovascular therapy of peripheral vascular disease.

More than 200 million people worldwide have peripheral artery disease (PAD) or its most severe manifestation, critical limb ischemia (CLI). While endovascular treatment has become first line therapy in most cases, a number of challenges remain for optimal treatment of femoropopliteal (FP) or infrapopliteal (IP) disease, especially when these lesions are severely calcified, chronic total occlusions (CTOs) or in-stent restenosis (ISR). Continued evolution of technologies has significantly improved the outcomes for endovascular treatment. A number of new devices are in the pipeline right now, including new paclitaxel eluting stents and balloons, intravascular lithotripsy to treat severely calcified lesions, adventitial delivery of anti-restenotic agents to limit restenosis rates, and percutaneous femoro-popliteal bypass.

Emerging and Future Therapeutic Options for Femoropopliteal and Infrapopliteal Endovascular Intervention.

Despite recent advances in endovascular therapy for peripheral artery disease, current technologies remain limited by rates of long-term restenosis and application to complex lesion subsets. This article presents data on upcoming therapies, including novel drug-coated balloons, drug-eluting stents, bioresorbable scaffolds, novel drug delivery therapies to target arteries, techniques to limit postangioplasty dissection, and treatment of severely calcified lesions.