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101205 shape aha 2005 f

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101205 shape aha 2005 f

  1. 1. Zahi A. Fayad, PhD Associate Professor Imaging Science Laboratories Depts of Radiology and Medicine The Zena and Michael A. Wiener Cardiovascular Institute and The Marie-Josee and Henry R. Kravis Cardiovascular Health Center Mount Sinai School of Medicine, New York, NY 11-12-2005 AEHA - Shape Guidelines Dallas, Tx Noninvasive Molecular Imaging of Atherosclerosis With MRI - The Future Lies in Molecular Imaging, The question is which molecule
  2. 2. Choudhury RP; Fuster V; Fayad ZA Nature Drug Dev. 2004;3:913-925 Atherosclerosis: A Progressive Process Imaging Science Laboratories
  3. 3. Noninvasive Detection of Plaque Instability with Use of Radiolabeled (SPECT) Annexin A5 in Patients with Carotid-Artery Atherosclerosis Kietselaer BLJH et al. NEJM 350;14;April 1, 2004 •Left-Sided TIA 3 days before imaging •Annexin A5 hot spot •Annexin A5 staining •Right-sided TIA 3 months before imaging ªNo Annexin hot spot •No Annexing A5 staining
  4. 4. Davies JR, Rudd JH, Stroke 2005 in press Plaque Activity Assessment -18F-FDG- Macs PET/CT or PET/MR Rudd JHF et al. Circ 2002;105:2708-2711
  5. 5. • Paramagnetic (Iron) • Superparamagnetic (Gd) • Targeted Contrasts/Carriers Current Contrast-Enhanced MR Limited Plaque Activity Information Gd-chelate enhanced -non specific Targeted enhanced contrast agent - specific interaction with plaque Choudhury RP; Fuster V; Fayad ZA Nature Drug Dev. 2004 Aorta IVC Non specific Targeted
  6. 6. Molecular Imaging Contrast Agents Choudhury RP; Fuster V; Fayad ZA Nature Drug Dev. 2004 Lipinski MJ; Fuster V; Fayad ZA Nature Cardiovascular Medicine 2004 • Improve MR detection sensitivity • CA w high-relaxivity - e.g., small peptides • Increase payload of contrast agent • Targeted/Functional • Colloidal Carriers/Lipid based - Liposomes - microemulsions - micelles - lipoproteins • Targets
  7. 7. Age Characterization Using Fibrin-Targeted MR Contrast Agent in Chronic Thrombus 0 2 4 6 8 10 12 1 * P<0.01 Pre Acute 48 hours 1 week 2 weeks 3 weeks 4 weeks 6 weeks 8 weeks ContrasttoNoiseRatio(CNR) * * * 4 x Acute Thrombus 4 x 1-week-old Thrombus 10 x 8-week-old Thrombus 4 x 6-week-old Thrombus Sirol M; Fayad ZA et al. Atherosclerosis 2005:182:79-85 Sirol M; Fayad ZA et al. Circ 2005;112:1594-1600
  8. 8. MATRIX METALLOPROTEINASES TARGETING - Gd-peptide Approach IHC of atherosclerotic plaque for MMP2 MMP Zymography of aorta of ApoE mouse 40x 40x P947 (Guerbet) short peptide MMPs inhibitor 100 µmol/kg Amirbekian V; Fayad ZA et al. AHA 2005;D220 @ NOV 15 @ 4:45PM Imaging Science Laboratories NER P947 vs. P1135 0 0.5 1 1.5 2 2.5 3 1 2 3 4 5 Time-Point (1= Pre-Contrast;2= 1hr post;3= 2 hrspost;4 = 3hrs post;5= 22 hrspost) NER P947 External Standard P947 control P1135
  9. 9. Lipid-Based Particulates Lipoproteins: Chylo, VLDL, TG, LDL, HDL • Gd, Iron, Fluorescents, etc. • Ab, peptide, etc.
  10. 10. In Vivo Aortic Atherosclerotic Plaque in ApoE-KO Mice Gd Immunomicelles Macrophages scavenger receptor types I&II Murine (CD204) 9.4T TR=500 ms; TE= 8.6 ms 101 µm in plane spatial resolution 500 µm slice thickness Injected - 13.7µmol/kg Mφ A C Amirbekian V; Fayad ZA et al.; AHA 2005;Nov 15;D220 @2pm Imaging Science Laboratories
  11. 11. Sirol M; Fayad ZA et al. Circulation. 2004;109:2890-2896 Sirol M; Fayad ZA et al. AHA 2005 Nov 15 D220 @ 2:45 pm Atherosclerotic Plaques Detected by Gadofluorine-Enhanced In Vivo MRI Imaging Science Laboratories
  12. 12. Gadofluorine M Plaque MR ApoE-KO mouse lesions • Yellow - localization in ECM (tenascin) • No cellular uptake Mφ Lymphocytes Smooth muscle cells mAb (green) Gadofluorine-carbocyanin conjugate (red) DAPI cell nuclei (blue) Sirol M; Fayad ZA et al. AHA 2005 NOV 15 D220;4:30PM 9.4T TR=500 ms; TE= 8.6 ms 101 µm in plane spatial resolution 500 µm slice thickness 100µmol/Kg (gadofluorine M)
  13. 13. Kelly KA, Weissleder R et al. Circ Res. 2005;96:327-336. Multimodal CLIO-Cy5.5-VCAM-1 Peptide (Iron-peptide) TARGETED SUPERPARAMAGNETIC NP Amino-Cross-linked Iron Oxide =Amino-CLIO
  14. 14. In vivo Macrophage Imaging Using Iron Oxide Particles in Atherosclerotic Rabbits GRASP (white spots)T2* GRE (dark spots) 24h POST CONTRAST
  15. 15.  Lipoprotein carrier  Natural Affinity to plaques  Small size (7-12 nm)  Does not trigger immune reactions  Easily reconstituted  Efficient drug carrier Frias JC et al. J. Am. Chem. Soc. 2004 126(50): p. 163-167 HDL Properties
  16. 16. ApoA-I DMPE-NBD (optical) Unesterified Cholesterol Cholesterol Ester Gd-DTPA- DMPE (MRI) Triglyceride Phospholipid r1p = 10.4 mM-1 s-1 (1.5 T, 25 °C) Imaging Science LaboratoriesFrias JC et al. J. Am. Chem. Soc. 2004 126(50): p. 163-167
  17. 17. 119 98 52 37 30 22 apoA-I H D L rH D L + Gd-D T PA -D M PE kDa GdGd-DTPA-DMPE-DTPA-DMPE rr1p1p = 10.4 mM= 10.4 mM-1-1 ss-1-1 (1.5 T, 25(1.5 T, 25 °°C)C) 4-12% SDS-PAGE DPPE-NBD HN O O P O OH O H O O O NO2 N O N 14 14 reconstitutiondelipidation Control N N H O O O P O OH O H O O O N O N O O O O O OO Gd J. C. Frías et al., J. Am. Chem. Soc., 2004, 126, 16316 12 12
  18. 18. 0 10 20 30 40 50 60 0 10 20 30 40 50 60 70 80 Fraction number Abs280nm rHDL-sphe rHDL-disc apoE-KO plasma (x10) incubated HDL VLDL LDL IDL HDL Cholesterol estersTriglycerides Gadolinium complex Phospholipids ApoA-I Reconstituted hollow spherical HDL Reconstituted discoidal HDL Native incubated HDL
  19. 19. Pre-contrast 48 hours post-contrast1 hr post-contrast 24 hr post-contrast ApoE-KO mice; 4.36 mmol/kg @ 9.4-T MRM rHDL-Gd-DTPA-DMPE Frias JC et al. J. Am. Chem. Soc. 2004 126(50): p. 163-167 DAPI srHDL-NBD CD68:RPE Mφ rHDL for Plaque Detection in ApoE KO Mice
  20. 20.  Silvia Aguiar, MD  Gilbert Aguinaldo, MD  Vardan Amirbekian  Lucy Feliciano  JC Frias, PhD  Fabien Hyafil, MD  Vitalii Itskovich, PhD  Alex Leber, MD  Enric Lopez, MD, PhD  Michael Lipinski  Frank Macaluso, RT  NIH/NHLBI R01HL71021; R01HL78667; R43HL71470  Intellectual Property Managed by Mount Sinai  Venkatesh Mani, PhD  Lena Mara  Gabor Mizsei, MS  Dan Samber, MS  Karen Saebo, PhD  Marc Sirol, MD  Cheuk Tang, PhD  Hiraoki Taniguchi, MD  Esad Vucic, MD  Karen Weinshelbaum Imaging Science Laboratories (ISL) Mount Sinai School of Medicine
  21. 21.  Valentin Fuster, MD, PhD  Donald Smith, MD  Jonathan Halperin, MD  Pedro Moreno, MD  K-R Purushothaman, MD  Michael Farkouh, MD  Mary Ann McLaughlin, MD  Jeffrey Olin, MD  Alison Schecter, MD Radiology  Burton Drayer, MD  Zvi Lefkovitz, MD  Bradley Delman, MD  Emil Cohen, MD CVI  Jesse Weinberger, MD  Stanley Tuhrim, MD Neurology  Sanjay Rajagopalan, MD  Javier Sanz, MD  Santo Dellegrottaglie, MD Clinical CMR/CT Mount Sinai School of Medicine Collaborators  Edward A. Fisher, MD, PhD  John Postley, MD  Carlton Boxhill, MD  Lisa Hudgings, MD  Christine Williams, MD  Tom Starc, MD  Sam Gidding, MD  Kevin Williams, MD  Yukihiko Momiyama, MD  Jean-Francois Toussaint, MD, PhD Pathology  John T. Fallon, MD, PhD Pediatrics  Jeff Saland, MD
  22. 22. The following relationships exist related to this presentation: SOME CONTRAST AGENTS DISCUSSED ARE NOT FDA APPROVED Presenter Disclosure Information  NIH/NHLBI R01HL71021; R01HL78667; R43HL71470  Siemens Medical Solutions  Pfizer/GE HealthCare  Guerbet  Schering  Society of Atherosclerosis Imaging (www.SAI.ORG) President  Society of Cardiovascular Magnetic Resonance Board Member  Intellectual Property Managed by Mount Sinai

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