Liposomal codelivery of inflammation inhibitor and collagen protector to the plaque for effective anti-atherosclerosis

摘要

Plaque plays a central role in atherosclerosis(AS)progression,whereas inflammation and destruction of the plaque microenvironment contribute to plaque advancement.As a result,a therapy regime,which combines anti-inflammation and inhibition-degradation of plaque matrix,appears to be a promising strategy to combat AS.Herein,we report a p H-sensitive liposome co-loading with the anti-inflammatory agent(oridonin,ORD)and plaque-collagen protector(marimastat)for anti-AS therapy.ORD was first conjugated with hyaluronic acid(HA)to target the inflammation contributor,pro-inflammatory macrophages.Then,the conjugate assembled onto the MATT-loaded liposomes.The co-loaded system(150 nm)significantly improved pharmacokinetics over the liposomes without anchoring the conjugate and accumulated effectively in the plaque.The preparation administration allowed efficient anti-AS activities in high-fat diet(HFD)-Apoe-/-mice by decreasing the pro-inflammatory cytokine expression in the serum,lessening the lesion area,alleviating the plaque collagen degradation,promoting macrophage polarization from phenotypic M1 to M2,reducing T helper(Th)17 cells(Th17)/T regulatory cells(Tregs)and Th1/Th2 ratio,etc.Furthermore,the serum determination in AS patients demonstrated high expression of the inflammatory cytokines,indicating our finding may offer a potential guideline for clinical practice.