Anti-inflammatory nanoparticle formulations to treat atherosclerosis

简介(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)是西方世界主要的死亡原因。预防战略目前侧重于控制危险因素和血脂水平。即使在完全达到治疗目标的情况下，仍有很高的残留风险。在人类中，渗透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，斑块炎症被认为是降低动脉粥样硬化血栓形成事件复发率的治疗目标。他汀类药物已知具有多效性抗炎作用，但为了开发和扩大这些作用，新的配方 有效地靶向斑块并在靶组织中高浓度积聚药物的方法需要开发。与他汀类药物类似，大麻类化合物也显示出强大的抗炎特性。大麻类化合物是一类疏水化合物，可以激活大麻素受体1(CB1)或CB2受体。为了在动脉粥样硬化疾病的背景下更好地利用这两类药物，纳米粒制剂提供了显著的优势，包括减少全身或精神药物效应，同时通过局部动脉粥样硬化斑块给药提高疗效和生物利用度。在这种情况下，脂蛋白纳米颗粒可能非常适合，因为它们可以携带有效的脂类药物，并自然地靶向动脉粥样硬化斑块巨噬细胞。上述纳米颗粒平台将使用微流控技术生产。将进行全面的体外靶向和疗效研究。在体内，将在传统的动脉粥样硬化小鼠模型和心肌梗死加重的动脉粥样硬化小鼠模型上进行生物分布和成像辅助治疗研究。广泛的免疫荧光、组织学和分子生物学技术将被应用于评估体内的发现并揭示其作用机制。具体目标是：目标1：利用微流控技术创建载药脂蛋白纳米粒文库。目的：通过成像研究这些脂蛋白纳米粒在动脉粥样硬化ApoE-KO小鼠体内的生物分布和斑块靶向性。目的：对动脉粥样硬化ApoE-KO小鼠进行高密度脂蛋白纳米治疗研究。目的：对心肌梗死加重的动脉粥样硬化小鼠进行高密度脂蛋白治疗研究。所有建议的纳米颗粒配方的单个成分都得到了FDA的批准，这一事实促进了向临床的转化。最后，范式的转变，即使用纳米颗粒制剂改变两类著名药物的药理作用，可能会对人类不同疾病的管理产生广泛而深远的影响。

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.