Inflammation in atherosclerotic plaque is a key promoter of acute vascular syndromes (i.e., thrombosis). Panoply of cytokines, growth factors, and immune cellular infiltrates converges to dramatically enhance the local thrombogenic potential of unstable plaques by creating a hypercoagulant, tissue factor-rich milieu that is exposed by either plaque rupture or erosion, which results in vessel occlusion and hypoxic tissue death. The overarching theme of our continuing multidisciplinary translational effort is the development and clinical testing of nanoparticle based approaches for the diagnosis and therapy of thrombotic cardiovascular diseases to detect, treat, and monitor unstable atheroma. The initial phase of the program was devoted to novel molecular imaging strategies that have culminated in FDA approved clinical trials of integrin-targeted nanoparticles for plaque angiogenesis detection. In the next phase of the work, we seek to develop and quantify the efficacy of new nanotherapeutic agents to attenuate plaque inflammation with the clinical goal of reducing the propensity toward thrombosis in acute vascular syndromes. We will evaluate the following overarching hypothesis: anti- inflammatory therapeutic nanoparticles can modulate the hyperthrombotic state in acute vascular syndromes and restore stability in atherosclerotic lesions with benefits over and above conventional therapy.
The specific aims are to: I. Design, formulate, and evaluate targeted anti-inflammatory nanotherapies in vitro II. Test therapeutic formulations in vivo in a standardized ApoE -/-mouse thrombosis model III. Test nanoparticle combinations and multiplexed nanoparticles in vivo for synergistic efficacy

Public Health Relevance

Inflammation in atherosclerotic plaque is a key promoter of acute vascular syndromes (i.e., thrombosis). The theme of this proposal is the development and testing of nanoparticle based approaches for the diagnosis and therapy of cardiovascular diseases to detect, treat, and monitor unstable atheroma. We seek to develop new molecularly targeted nanotherapies that interrupt inflammatory signaling molecules with the clinical goal of reducing the propensity toward thrombosis in acute vascular syndromes. These will be tested in vivo in mouse models as single agent and combination therapies.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL073646-10
Application #
8649065
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Buxton, Denis B
Project Start
2003-04-01
Project End
2017-03-31
Budget Start
2014-05-20
Budget End
2015-03-31
Support Year
10
Fiscal Year
2014
Total Cost
$667,101
Indirect Cost
$228,219
Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Yan, Huimin; Duan, Xin; Pan, Hua et al. (2016) Suppression of NF-?B activity via nanoparticle-based siRNA delivery alters early cartilage responses to injury. Proc Natl Acad Sci U S A 113:E6199-E6208
Yan, Huimin; Zhou, Hui-Fang; Akk, Antonina et al. (2016) Neutrophil Proteases Promote Experimental Abdominal Aortic Aneurysm via Extracellular Trap Release and Plasmacytoid Dendritic Cell Activation. Arterioscler Thromb Vasc Biol 36:1660-1669
Palekar, Rohun U; Jallouk, Andrew P; Myerson, Jacob W et al. (2016) Inhibition of Thrombin With PPACK-Nanoparticles Restores Disrupted Endothelial Barriers and Attenuates Thrombotic Risk in Experimental Atherosclerosis. Arterioscler Thromb Vasc Biol 36:446-55
Palekar, Rohun U; Vemuri, Chandu; Marsh, Jon N et al. (2016) Antithrombin nanoparticles inhibit stent thrombosis in ex vivo static and flow models. J Vasc Surg 64:1459-1467
Esser, Alison K; Schmieder, Anne H; Ross, Michael H et al. (2016) Dual-therapy with ?v?3-targeted Sn2 lipase-labile fumagillin-prodrug nanoparticles and zoledronic acid in the Vx2 rabbit tumor model. Nanomedicine 12:201-11
Chen, Junjie; Vemuri, Chandu; Palekar, Rohun U et al. (2015) Antithrombin nanoparticles improve kidney reperfusion and protect kidney function after ischemia-reperfusion injury. Am J Physiol Renal Physiol 308:F765-73
Palekar, Rohun U; Jallouk, Andrew P; Lanza, Gregory M et al. (2015) Molecular imaging of atherosclerosis with nanoparticle-based fluorinated MRI contrast agents. Nanomedicine (Lond) 10:1817-32
Hou, Kirk K; Pan, Hua; Schlesinger, Paul H et al. (2015) A role for peptides in overcoming endosomal entrapment in siRNA delivery - A focus on melittin. Biotechnol Adv 33:931-40
Wagner, Elizabeth M; Jenkins, John; Schmieder, Anne et al. (2015) Angiogenesis and airway reactivity in asthmatic Brown Norway rats. Angiogenesis 18:1-11
Jallouk, Andrew P; Palekar, Rohun U; Pan, Hua et al. (2015) Modifications of natural peptides for nanoparticle and drug design. Adv Protein Chem Struct Biol 98:57-91

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