Multivalent Theranostics for Vascular Imaging and Therapy Project Summary Non-invasive approaches for functional assessment of atherosclerosis present an opportunity for intervention in cardiovascular disease. In our preliminary studies, we have successfully employed multimodal vesicles (fluorescence and magnetic resonance imaging, MRI) containing key engulfment ligands of M?to enable preferential imaging of these cells in atherosclerosis. Our method takes advantage of macrophage engulfment of agents, allowing prolonged retention of MRI signal in the atherosclerotic vessel wall. In this proposal, we hypothesize that immunoliposomes based on these principles containing antibodies against myeloid related protein-8/14 (MRP), shown to be a key mediator of inflammation and injury by our group, will facilitate imaging, alter M?phenotype, enhance anti-inflammatory effects, while minimizing off-target side effects of therapeutic agents. In this proposal we suggest a series of structured studies in relevant models of inflammation and atherosclerosis (ApoE-/- and ApoE-/-MRP14-/-).
In Aim 1, we will test the ex-vivo and in-vivo theranostic properties of PEG protected Gd-containing fluorescently-tagged immunoliposomes against MRP (antiMRP-CC- L). Spatial localization, targeting and optimization will be carried out in organoid cultures and short-term wire- injury models.
In Aim 2, we will synthesize and test theranostic immunoliposomes and hypothesize that immunoliposomes validated in Aim 1 and additionally containing a PPAR? agent (?-antiMRP8/14-CC-L) represents an attractive approach that combines locus specific delivery with synergistic therapeutic effects of PPAR? agents on M?function. As part of this aim, we will investigate biodistribution and pharmacokinetics of several doses of an optimized ?-antiMRP-CC-L in ApoE-/- and will additionally test the feasibility of in-vivo imaging in inflammation. The effects on M?phenotype and function will be evaluated by assessing M? surface markers, cytokines and inflammatory gene expression. We propose well designed experiments that will allow assessment of imaging performance, therapeutic effects including mechanisms of action that will shed unique insights into the roles of MRP and therapeutic synergism with M?specific delivery of high-affinity PPAR? ligands. The utilization of clinically approved Gd preparations, high Gd-payload/particle and homology of MRP in mice and humans confers immediate translational relevance. We envision that strategies combining M?targeted imaging probes and therapies has the potential for use in a variety of inflammatory diseases.
Atherosclerosis is the leading cause of morbidity and mortality worldwide. Plaque build-up within arteries and instability of the plaque result in the cardiovascular events such as heart attacks and stroke. Instability of the plaque is related to progressive accumulation of white blood cells that result in synthesis of substances that are deleterious to the blood vessel. In this proposal, we propose building novel drug delivery systems that will allow imaging using magnetic resonance imaging (MRI) and at the same time accomplish delivery of high concentrations of drugs to specific areas of the plaque where white cells reside. In order to accomplish this, we propose in-vitro and in-vivo studies in susceptible atherosclerosis animal models to assess uptake, efficiency, pathways, therapeutic mechanisms and safety of agents to reduce inflammation and plaque. We envision that the strategies combining targeted imaging probes and therapies in a single platform has the potential to provide unique insights to plaque vulnerability and an opportunity for therapeutic intervention.
|Bagalkot, Vaishali; Badgeley, Marcus A; Kampfrath, Thomas et al. (2015) Hybrid nanoparticles improve targeting to inflammatory macrophages through phagocytic signals. J Control Release 217:243-55|
|Bandyopadhyay, Saibal; Xia, Xin; Maiseiyeu, Andrei et al. (2012) Z-Group ketone chain transfer agents for RAFT polymer nanoparticle modification via hydrazone conjugation. Macromolecules 45:6766-6773|
|Maiseyeu, Andrei; Badgeley, Marcus A; Kampfrath, Thomas et al. (2012) In vivo targeting of inflammation-associated myeloid-related protein 8/14 via gadolinium immunonanoparticles. Arterioscler Thromb Vasc Biol 32:962-70|
|Deiuliis, J A; Kampfrath, T; Ying, Z et al. (2011) Lipoic acid attenuates innate immune infiltration and activation in the visceral adipose tissue of obese insulin resistant mice. Lipids 46:1021-32|