Nanoparticle-based fluorescence molecular imaging Farouc Jaffer MD - - PowerPoint PPT Presentation

Nanoparticle-based fluorescence molecular imaging

Farouc Jaffer MD PhD Cardiovascular Research Center, Cardiology Division Massachusetts General Hospital, Harvard Medical School

Friday April 19, 2018. 08:40 – 10:10 SESSION: INNOVATIONS FOR PLAQUE IMAGING

Basis for Coronary Molecular Imaging

• Coronary plaque and stent complications remain leading causes of morbidity

and mortality worldwide

• Structural imaging of high-risk plaques (e.g. IVUS) currently do not predict

risk well enough to enable clinical action. The PROSPECT IVUS-VH trial showed a PPV of only 18% to predict ACS at 3 yrs.1

• Molecular imaging of coronary plaque biology offers a new approach to

understand drivers of plaque and stent complications2

• Noninvasive coronary molecular imaging approaches are limited by

resolution and motion

1Stone GW et al. NEJM 2011;364:226-35 2Mulder WJ, Jaffer FA, Fayad ZA, Nahrendorf M. Sci Transl Med 2014

• Optical imaging is in the Cath Lab: Optical

coherence tomography, near-infrared spectroscopy, angioscopy

• NIR window for fluorescence: ↓photon

attenuation (more light penetration) ↓autofluorescence (less background)

• NIRF Molecular Agents: Indocyanine green,

Prosense VM110, Bevacizumab-IR800; NIR Fluorecscent nanoparticles?

• Osborn et al. JACC CV imaging 2013;6:1327. Jaffer, Verjans. Heart 2014;100:1469; Bourantas et al. European Heart Journal 2017

Intravascular Near-Infrared Fluorescence (NIRF) Imaging: A High-Resolution Pathway To The Coronary Arteries

• -Weissleder, Ntziachristos Nat Med 2003
• -Kim,

Yoo.. Jaffer, T earney, Nat Med 2011

Nanoparticles (NPs) as molecular imaging platforms

Attributes

• Scale (1-100nm) facilitates NP interaction with cells
• Controllable physical properties and surface modifications

for ligand attachment, and longer circulation time

• Multimodal imaging capable
• Integrated therapeutic-diagnostics (“theranostics”)

Limitations

• Few are clinically approved
• Longer circulation time limits point-of-care applications

USPIO: Clinically Tested Nanomaterials for Imaging of Plaque Inflammatory Cells (Macrophages)

• USPIO: Ultrasmall super-paramagnetic

iron oxide (~30 nm)

• Targets plaque macrophages
• Strong R2>R1 effects
• Clinically tested N>300 pts; Long-

circulating; Peak CNR 36 hrs

PRE POST Iron Mac

ICA

• -Kooi et al. Circulation 2003; Trivedi et al.

Stroke 2004; Neurology 2006; Stroke 2007

* post * 5

VCAM-1

HCD STATIN

VCAM-1 dual-modal MRI-optical nanoparticles to assess anti- inflammatory atheroma therapy

160 240

• -Nahrendorf, Jaffer, Kelly..Weissleder Circulation 2006

Optical MRI

• VCAM-1 is an important

inflammation target

• Phage-display derived VCAM-1

targeting peptide

• USPIO scaffold derivatized with 8-

12 VCAM-1 targeting peptides

• Tested in ApoE-/- ± statin

Open questions: What atheroma cell populations are actually targeted by USPIO NPs? What mechanisms govern NP targeting in vivo?

• While most atheroma studies suggest Iron

Oxide NPs (USPIO) target macrophage, a number of studies suggest that non- macrophage atheroma cells are also available targets for USPIOs.

• As FDA-approved USPIOs such as Feraheme

are not fluorescent, we prepared a NIRF USPIO (CLIO-CyAm7) for investigation in vivo in atheroma-bearing rabbits susceptible to thrombosis

• - Jason McCarthy, MGH Center for Systems Biology

CLIO-CyAm7

WL

CLIO PBS

B

C

NIRF WL NIRF

A

CLIO

D C

PBS

E F

NIRF iron oxide NP targeting of atheroma

• N=31 NZW rabbits with

aortic atheroma

• IV CLIO-CyAm7 2.5-5.0

Fe/kg 24 hours before imaging

• Macroscopic

fluorescence reflectance imaging and fluorescence microscopy demonstrates uptake in atheroma

• - Stein-Merlob AF, Hara et al. Circulation: Cardiovascular Imaging 2017

CD31 RAM11 aSMA

EC Mac SMC

L

L

M L L L

CD31 RAM11 aSMA CD31 RAM11 aSMA L L a S M A R A M 1 1 C D 3 1

Superficial Intima (2/3) Intimal- Medial Border (1/3)

CLIO-CyAm7 CLIO-CyAm7

A1 A2 A3 B1 B2 B3

• - Stein-Merlob AF, Hara et al. Circulation: Cardiovascular Imaging 2017

CLIO NP targets multiple plaque cell types; at the surface and in deeper areas of neovessels

EB CLIO AF

C A

H&E

E B D F

CLIO NP deposition occurs in areas of plaque permeability

• Subset of NZW rabbits
• IV CLIO-CyAm7 5.0 Fe/kg, 24

hours prior

• Co-injected with Evans Blue

permeability marker, 6 mL 0.5%, 30 minutes prior to sacrifice

• Strong relationship between

depth of penetration between CLIO and Evans Blue (r=0.64)

Thrombus

H

Pre-trigger Post-trigger Ex Vivo

*

Does CLIO NP deposition identify plaques susceptible to thrombosis?

• NZW rabbits with atheroma
• IV CLIO-CyAm7 2.5 Fe/kg, 24

hours prior

• Intravascular 2D NIRF molecular

imaging and IVUS

• Constantides model of triggered

thrombosis over 48h (RVV, histamine)

• Follow-up intravascular 2D NIRF

and IVUS at 48h

• - Stein-Merlob AF, Hara et al. Circ: Cardiovascular Imaging 2017

Thrombus Post

A B

RAM11

D E F

Carstairs’ CLIO AF

Pre Post

H C G

*

• - Stein-Merlob AF, Hara et al. Circulation: Cardiovascular Imaging 2017

CLIO-CyAm7 deposition is greater in plaques that develop thrombosis

• Triggered-

thrombosis

• IVUS and

Carstairs verified thrombosis in 67%

• Detailed

fluorescence microscopy

• Greater NP in

plaques with thrombosis

Conclusions

• Molecular imaging of NIR fluorescent iron oxide NPs reveal:
• NP deposition is modulated by plaque permeability
• NPs target macrophages, smooth muscle cells and

endothelial cells within atheroma

• NPs are more intensely localized in plaques that are

susceptible to triggered thrombosis

• NPs can be detected by intravascular NIRF catheters, offering

a pathway towards coronary artery detection of plaques predisposed to thrombosis.

Acknowledgements

Funding

• NIH R01 HL108229, R01 HL122388
• AHA Grant In Aid,
• HHMI Career Development Award
• Canon, Siemens, Merck, Kowa
• MGH CIMIT, SPARK, ECOR, CVRC grants
• MGH Hassenfeld Scholar Award

MGH-CSB Jason McCarthy Charles Lin Yoshi Iwamoto Claudio Vinegoni Ralph Weissleder BWH Cardiology Elena Aikawa Masanori Aikawa Eduardo Folco Hiroshi Iwata Amelie Vromann Peter Stone Peter Libby MGH CVRC/Cardiology Ion Botnaru Marcie Calfon Jie Cui (ASN) Amr El Maghraby Tetsuya Hara (AHA) Stephan Kellnberger (AHA) Chase Kessinger (T32) Jin Won Kim, Prof. Adam Mauskapf Eric Osborn (T32, KL2, K08) Ashley Stein-Merlob (HST 15, AHA) Johan Verjans (Rubicon) Ahmed Tawakol Technical University of Munich Dmitry Bozhko Vasilis Ntziachristos MGH Wellman Center for Photomedicine Hongki Yoo Giovanni Ughi Joe Gardecki Zhonglie Piao Kanwarpal Singh Gary Tearney MGH Vascular Surgery Richard Cambria

• Univ. of Michigan

Peter Henke MIT Aditya Kalluri Elazer Edelman

Farouc Jaffer MD PhD fjaffer@mgh.harvard.edu; @faroucjaffer

Thank you for your attention