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Zahi A. Fayad, PhDAssociate Professor
Imaging Science Laboratories
Depts of Radiology and MedicineThe Zena and Michael A. Wiener
Cardiovascular Institute and The Marie-Josee and Henry R. Kravis Cardiovascular
Health CenterMount Sinai School of Medicine, New York,
NY
11-12-2005 AEHA - Shape GuidelinesDallas, Tx
Noninvasive Molecular Imaging of AtherosclerosisWith MRI - The Future Lies in Molecular Imaging,
The question is which molecule
Choudhury RP; Fuster V; Fayad ZA Nature Drug Dev. 2004;3:913-925
Atherosclerosis: A Progressive Process
Imaging Science Laboratories
Noninvasive Detection of Plaque Instabilitywith 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
imagingªNo Annexin hot spot
•No Annexing A5 staining
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
• Paramagnetic (Iron)• Superparamagnetic (Gd)• Targeted Contrasts/Carriers
Current Contrast-Enhanced MR LimitedPlaque 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
Molecular Imaging Contrast Agents
Choudhury RP; Fuster V; Fayad ZA Nature Drug Dev. 2004Lipinski 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
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
Con
tras
t to
Noi
se R
atio
(CN
R)
*
*
*
4x
Acute Thrombus
4x
1-week-old Thrombus
10x
8-week-old Thrombus
4x
6-week-old Thrombus
Sirol M; Fayad ZA et al. Atherosclerosis 2005:182:79-85Sirol M; Fayad ZA et al. Circ 2005;112:1594-1600
MATRIX METALLOPROTEINASES TARGETING - Gd-peptide Approach
IHC of atherosclerotic plaque for MMP2
MMP Zymography ofaorta of ApoE mouse
40x
40x
P947 (Guerbet) short peptide MMPs inhibitor100 mol/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 = 1 hr post; 3 = 2 hrs post; 4 = 3 hrs post; 5 = 22 hrs post)
NER
P947 ExternalStandard
P947
control
P1135
Lipid-Based Particulates
Lipoproteins: Chylo, VLDL, TG, LDL, HDL
• Gd, Iron, Fluorescents, etc.• Ab, peptide, etc.
In Vivo Aortic Atherosclerotic Plaque in ApoE-KO MiceGd Immunomicelles Macrophages scavenger receptor types
I&II Murine (CD204)
9.4T TR=500 ms; TE= 8.6 ms101 m in plane spatial resolution500 µm slice thickness
Injected - 13.7µmol/kg
M
A
C
Amirbekian V; Fayad ZA et al.; AHA 2005;Nov 15;D220 @2pm
Imaging Science Laboratories
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
Gadofluorine M Plaque MR ApoE-KO mouse lesions
• Yellow - localization in ECM (tenascin)• No cellular uptake
M
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 ms101 m in plane spatial resolution500 µm slice thickness100µmol/Kg (gadofluorine M)
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
In vivo Macrophage Imaging Using Iron Oxide Particles inAtherosclerotic Rabbits
GRASP (white spots)T2* GRE (dark spots)
24h POST CONTRAST
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
ApoA-I
DMPE-NBD(optical)
UnesterifiedCholesterol
CholesterolEster
Gd-DTPA-DMPE(MRI)
Triglyceride
Phospholipid
r1p = 10.4 mM-1s-1 (1.5 T, 25 °C)
Imaging Science LaboratoriesFrias JC et al. J. Am. Chem. Soc. 2004 126(50): p. 163-167
119 98
52
37
30
22
apoA-I
HDL
rHDL + Gd-DTPA-DMPE
kDaGdGd-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
HNO O
P
O
OHO
H O
O
O
NO2
NO
N
14
14
reconstitutiondelipidation
Control
NNH
O
O
OP
O
OHO
H O
O
O
N
O
N
O OO
O O
OO
Gd
J. C. Frías et al., J. Am. Chem. Soc., 2004, 126, 16316
12
12
0
10
20
30
40
50
60
0 10 20 30 40 50 60 70 80
Fraction number
Abs
280
nm
rHDL-spherHDL-discapoE-KO plasma (x10)incubated HDL
VLDL
LDL IDL HDL
Cholesterol estersTriglyceridesGadolinium complex
Phospholipids
ApoA-I
Reconstituted hollowspherical HDL
Reconstituteddiscoidal HDL
Native incubated HDL
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:RPEM
rHDL for Plaque Detection in ApoE KO Mice
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
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
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