Perspectives and Opportunities for Nanomedicine in the Management of Atherosclerosis
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1 Perspectives and Opportunities for Nanomedicine in the Management of Atherosclerosis Zahi A. Fayad, PhD, FAHA, FACC Professor of Radiology and Medicine (Cardiology) Director, Translational and Molecular Imaging Institute Mount Sinai School of Medicine, New York, NY August 26, ESC, Munich
2 Disclosures Funding American Heart Association fellowship (DPC) K99 EB (DPC) NHLBI R21 HL (KSB) NIH/NCRR S10RR02656 & S10RR (CYT) NIH R01 HL071021, HL and EB009638; NIH/NCRR UL1RR029887; NHLBI HHSN C (ZAF)
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6 Cardiovascular nanotechnology: the opportunity Combine power of innovation in nano-materials and CV biology to develop new solutions in cardiovascular disease Detect disease before health has deteriorated - Sensors - Imaging Deliver therapeutics - Local delivery - Improved efficacy - Post-therapy monitoring Develop research tools to enhance understanding of the disease
7 Cardiovascular nanotechnology: the opportunity Tang J et al. Curr. Cardiovasc. Imaging Reports 2011 Lobatto M et al. Nature Reviews Drug Discovery 2011
8 Molecular imaging in atherosclerosis Leuschner & Nahrendorf, Circ Res 2011 Buxton DB et al. Circ 2011; 123:
9 Osborn EA & Jaffer F JACC Imaging 2012
10 Molecular Imaging in vivo characterization and measurement of biologic processes at the cellular and molecular level [via imaging] - Weissleder and Mahmood, 2001, Radiology targeting group contrast generating substance
11 Cardiovascular nanotechnology: the opportunity Lipid-based nanoparticles Allows a modular approach to particle assembly Straightforward synthesis WJM Mulder et al, Acc. Chem. Res., 2009, 42, 7,
12 Biodistribution <5.5 nm cleared by kidneys >100 nm taken up by Kupffer cells Nel AE et al. Nat Mat 2009
13 Lobatto et al. Nat Rev Drug Discov Nanoparticle targeting in atherosclerosis
14 Why use lipoproteins as contrast agents? Lipoproteins have important biological functions in the body Lipoproteins are heavily involved in atherosclerosis Lipoprotein receptors are often overexpressed in tumors Involvement in other diseases, such as hypercholesterolemia Natural (non-immunogenic) and biodegradable
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16 HDL: a contrast/drug delivery platform MRI contrast agent Fluorescence CT contrast agent Targeted drug delivery
17 HDL: a contrast/drug delivery platform MRI contrast agent Fluorescence CT contrast agent Targeted drug delivery
18 Nanoparticle Drug Delivery Enhanced circulation half-life Protection from inactivation and interactions with plasma constituents Minimizing systemic exposure of the drug Favourable biodistribution profiles Local accumulation and retention Decreasing dose, altering mode of action and minimizing adverse effects -> Improved efficacy
19 Kamaly N et al. Chem Soc Rev 2012 Timeline of Clinical Stage Nanomedicine Firsts in Oncology
20 Potential and Challenges Buxton DB et al. Circ 2011; 123:
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22 Large-Scale Production of HDL Nanoparticles
23 Microfluids produced HDL-NPs Macrophage Subclasses Uptake
24 High Risk Patients: New Treatment Paradigm Acute IV-Rx Routine Rx Rapid plaque stabilization/regression Short term risk reduction Routine Rx Complement routine Rx: PCI risk factors reduction, such as statins, antiplatelet and blood pressure Rx Long term plaque stabilization/regression Long term risk reduction Modified from PK Shah Future Lipidol 2006
25 Corticosteroids: Effect on Atherosclerosis Corticosteroids exhibit an anti-inflammatory pharmacological effect Prevent plaque formation and restenosis in preclinical models Poon et al. Atherosclerosis 2001 Ribichini et al. JACC 2007 Willem J.M. Mulder However: Not clinically suitable because: High and frequent dosing required Non specific, low efficacy, adverse effects
26 Liposomal glucocorticoids Liposomal glucocorticoids Enhanced circulation half-life Protection from inactivation and interactions with plasma constituents
27 Nanoparticle (NP)-glucocorticoids (1 injection) with imaging used to evaluate efficacy - FDG-PET/CT Liposomal glucocorticoids Enhanced circulation half-life Protection from inactivation and interactions with plasma constituents Lobatto M et al. Molecular Pharmaceutics 2010 NP Free
28 Correlation with Histology Lobatto M et al. Molecular Pharmaceutics 2010 Willem J.M. Mulder
29 Statins have anti-inflammatory pleiotropic effects Statins are potent cholesterol-lowering drugs Anti-inflammatory effects are independent of their cholesterol-lowering capability Modulation of macrophages is a major contributor to anti-inflammatory effects HDL drug delivery
30 Statins have high liver uptake and low bioavailability to atherosclerotic macrophages Corsini et al. Pharmacol Therapeut 1999 HDL drug delivery
31 HDL is a natural nanoparticle HDL binds to macrophages via ABCA1, ABCG1 and SR-B1 receptors [S]-rHDL mimics natural HDL [S]-rHDL could be loaded with imaging labels HDL drug delivery Statin loaded rhdl nanoparticles ([S]-rHDL) target atherosclerotic macrophages
32 HDL drug delivery [S]-rHDL inhibits atherosclerosis progression N=32 (8 per group)
33 Aggressive [S]-rHDL nanotherapy induces plaque regression by depleting macrophages in plaques 4x for 1 week
34 NIH/NHLBI Program of Excellence in Nanotechnology (PEN)
35 MSSM Valentin Fuster Burton Drayer Michael Farkouh Jagat Narula Bachir Taouli Matthew Cham Willem Mulder David Cormode Venkatesh Mani Claudia Calcagno Wei Chen Torjus Skajaa June Tang Raphael Duivenvoorden Acknowledgements Funding American Heart Association fellowship (DPC) K99 EB (DPC) NHLBI R21 HL (KSB) NIH/NCRR S10RR02656 & S10RR (CYT) NIH R01 HL071021, HL and EB009638; NIH/NCRR UL1RR029887; NHLBI HHSN C (ZAF) NYU Edward Fisher Cambridge University James Rudd Ziad Mallat MGH Ahmed Tawakol UCSD Sam Tsimikas MIT Bob Langer AMC John J.P. Kastelein Eric Stroes WUSTL Gwen Randolph MSSM Pathology Lab (TEM) Ronald Gordon Heather Bell
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