Anti-inflammatory nanoparticle formulations to treat atherosclerosis

描述（由申请人提供）：动脉粥样硬化及其主要临床表现冠状动脉疾病（CAD）是西方世界的主要死亡原因。目前的预防策略侧重于控制危险因素和血脂水平。即使完全达到治疗目标，实质性的残余风险仍然很高。在人类中，浸润斑块的单核细胞分化为炎性巨噬细胞，产生蛋白水解酶，消化细胞外基质，导致斑块破裂。因此，斑块炎症被视为降低动脉粥样硬化血栓事件复发率的治疗靶点。他汀类药物具有已知的多效抗炎作用，但为了利用和扩大这些作用，需要新的配方

DESCRIPTION (provided by applicant): Atherosclerosis and its major clinical manifestation, coronary artery disease (CAD), is the leading cause of death in the western world. Preventive strategies currently focus on controlling risk factors and lipid levels. Substantial residual risk remains high, even when treatment goals are fully met. In humans, monocytes that infiltrate the plaque differentiate into inflammatory macrophages produce proteolytic enzymes that digest extracellular matrix causing plaque rupture. Plaque inflammation is therefore pursued as a therapeutic target to lower the recurrent rates of atherothrombotic events. Statins have known pleiotropic anti-inflammatory effects, but to exploit and amplify these effects, novel formulations that effectively target plaques and accumulate the drug at high concentration in target tissue need to be developed. Similarly to statins, cannabinoids, a class of hydrophobic compounds that can activate either the cannabinoid receptor 1 (CB1) or CB2 receptor, have shown potent anti-inflammatory properties as well. To better exploit both drug classes in the context of atherosclerotic disease, nanoparticle formulations offer significant advantages, including the reduction of systemic or psychotropic effects, while simultaneously increasing the efficacy and bioavailability through local atherosclerotic plaque drug delivery. In this context, lipoprotein nanoparticles may be excellently suited as they can carry payloads of lipophilic drugs and naturally target atherosclerotic plaque macrophages. The aforementioned nanoparticle platforms will be produced using microfluidics. Full in vitro targeting and efficacy studies will b performed. In vivo, biodistribution and imaging-assisted therapeutic studies will be performed on a traditional mouse model of atherosclerosis as well as an myocardial infarction aggravated mouse model of atherosclerosis. Extensive immunofluorescent, histological, and molecular biological techniques will be applied to evaluate the in vivo findings and to unravel the mechanism of action. The specific aims are: Aim 1: To create a library of drug-loaded lipoprotein nanoparticles using microfluidics. Aim 2: To study the biodistribution and plaque targeting of these lipoprotein nanoparticles in atherosclerotic ApoE-KO mice via imaging. Aim 3: To conduct a HDL nanotherapy study in atherosclerotic ApoE-KO mice. Aim 4: To conduct a HDL therapy study in mice with MI-aggravated atherosclerosis. Translation to the clinic is facilitated by the fact that the individual components of all the proposed nanoparticle formulations are FDA approved. Finally, the paradigm shift, i.e. using nanoparticle formulations to alter the pharmacological effects of two well-known drug classes could have a broad and profound impacts on the management of different human diseases.