Application of a mechanically responsive, inflammatory macrophage-targeted dual-sensitive hydrogel drug carrier for atherosclerosis

Atherosclerotic lesions create obvious vascular stenosis due to the presence of plaque, and a large number of inflammatory macrophages are enriched in the thrombus. In this study, we develop a composite hydrogel drug delivery system that is capable of both mechanically-sensitive drug release and of targeting inflammatory macrophages at the thrombus. The hydrogel is a high molecular weight hyaluronic acid (HA) modified with glycidyl methacrylate as a hydrogel precursor; a cross-linkable block copolymer (CBC) is used as the drug coating material and a microscopic cross-linking agent. The difference in drug release rate of the composite hydrogel (HACBC) in simulated blood vessels with 0 % and 75 % occlusion was as high as 49.3 %. Under long-term cycling conditions in stenotic vessels, dynamic shear rheometry revealed that the HACBC still maintained the hydrogel properties. However, the micelles were deformed and recombined to produce smaller sized micelles. An in vitro cell culture demonstrated precise targeting of the HACBC to inflammatory macrophages, and our rabbit experiments with simvastatin-coated HACBC confirmed the effective release of simvastatin in the plaque of the drug carrier. Moreover, we demonstrated the precise targeting of HACBC in vivo in apoE-/- mice by using HACBC coated with cy7. The mechanical stress-sensitive and CD44 receptor-targeted dual-response drug delivery system prepared by micellar composite hydrogel is the first application in the field of atherosclerosis, which provides a new method for diagnosing and treating atherosclerosis.