Inflammation is well recognized as the underlying mechanism in a multitude of acute and chronic diseases, from injury to pain to cancer. This research proposes to design theranostic nanoemulsion-based agents that have capabilities for imaging by positron emission tomography (PET), near-infrared fluorescence (NIRF) optical and magnetic resonance imaging (MRI), and for treating inflammation. The theranostic nanoemulsions will target macrophages, as they simultaneously deliver a COX-2 inhibitor drug (celecoxib), positron emitting radionuclides and a NIRF dye. The core of the nanoemulsion is perfluorocarbon (PFC), which allows for 19F- MRI. The agents developed in this project will lead to broadly applicable treatment and diagnostic strategies for inflammation driven diseases. The PFC nanoemulsion platform (droplet size of 100-150 nm) incorporates hydrophobic small molecule drugs and has a lipid/PEG outer shell that can be readily modified with chelators for labeling with metal radionuclides such as 64Cu and 89Zr. We previously demonstrated that based on its size (120-140 nm) and surface properties, this nanoemulsion specifically targets macrophages and can deliver poorly soluble small molecule anti-inflammatory drugs (e.g. COX-2 inhibitor celecoxib) to sites of inflammation in rodent models. Preliminary data show these nanoemulsions reduce inflammation in mice while producing inflammation specific NIRF images of the drug-induced changes of macrophage trafficking in vivo. We hypothesize that addition of chelators for complexation of Cu-64 and Zr-89 for PET imaging will be highly translatable for human imaging to monitor drug delivery.
The specific aims will focus on strategies for synthesis of chelators-nanoemulsion constructs that incorporate drugs and PET radionuclides and their characterization in vitro (Aim 1). PET imaging and biodistribution, as well as proof-of-principle validation of the nanoemulsion- mediated drug delivery and efficacy will be performed in a mouse model of inflammation (Aim 2). If successful, we will have a lead theranostic nanoemulsion for PET and drug delivery that can be further examined in models of cancer, pain and other disease states where inflammation plays a major role in morbidity, as part of a future R01 application.
Inflammation is the cause of a multitude of acute and chronic diseases, and there is a need to deliver treatment in the form of drugs or radionuclides, and to be able to visualize where the treatment is being delivered. We will develop nanoemulsions that have the capability to simultaneously treat inflammation by delivering drugs and image inflammation with positron emission tomography (PET), in a mouse model of chemically induced inflammation.
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