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.
In this project we propose the development of lipoprotein nanoparticle formulations of statins and cannabinoids for the treatment of atherosclerosis. Nanoparticle libraries will be created and therapeutic efficacy will be evaluated on cell lines in vitro, as well as atherosclerosis mouse models using in vivo imaging and ex vivo histological techniques. We expect our approach to have a broad and profound impact on the management of atherosclerotic disease.