Multifunctional pathology-mapping theranostic nanoplatforms for US/MR imaging and ultrasound therapy of atherosclerosis

Abstract

Atherosclerotic thrombosis is the leading cause of most life-threatening cardiovascular diseases (CVDs), particularly as a result of rupture or erosion of vulnerable plaques. Rupture or erosion-prone plaques are quite different in cellular composition and immunopathology, requiring different treatment strategies. The current imaging technology cannot distinguish the types of vulnerable plaques, and thus empirical treatment is still applied to all without a tailored and precise treatment. Herein, we propose a novel strategy called “Multifunctional Pathology-mapping Theranostic Nanoplatform (MPmTN)” for the tailored treatment of plaques based on the pathological classification. MPmTNs are made up of poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs), containing contrast imaging materials Fe₃O₄ and perfluoropentane (PFP), and coated with specific plaque-targeted peptides PP1 and cyclic RGD. The PFP encapsulated inside the MPmTN can undergo a phase change from nanodroplets to gas microbubbles under therapeutic ultrasound (TUS) exposure. The acoustic and biological effects induced by TUS and disruption of microbubbles may further promote therapeutic effects. Hypothetically, MPmTN NPs can target the rupture-prone plaque via the binding of PP1 to class A scavenger receptors (SR-A) on macrophages, induce the apoptosis due to TUS exposure and thus reduce the chronic soakage of inflammatory cells. The MPmTN NPs can also target the erosion-prone plaque through the binding of cRGD to glycoprotein (GP) IIb/IIIa on activated platelets and promote platelet disaggregation under TUS exposure. Therefore, MPmTNs may work as a multifunctional pathology-mapping therapeutic agent. Our in vitro results show that the MPmTN with PP1 and cRGD peptides had a high binding affinity both for activated macrophages and blood clots. Under TUS exposure, the MPmTN could effectively induce macrophage apoptosis, destroy thrombus and exhibit good imaging properties for ultrasound (US) and MRI. In apoE^−/− mice, MPmTNs can selectively accumulate at the plaque site and reduce the T₂-weighted signal. The apoptosis of macrophages and disaggregation of activated platelets on the plaques were also confirmed in vivo. In summary, this study provides a potential strategy for a tailored treatment of vulnerable plaques based on their pathological nature and a multimodal imaging tool for the risk stratification and assessment of therapeutic efficacy.