SHAPE Society

1. Editorial Slides
VP Watch, March 19, 2003, Volume 3, Issue 11
Nanotechnology Promises Combined
Molecular Imaging and Therapy for
Vulnerable Plaques

2. –Nanotechnology is a burgeoning field
with unique applications for
molecular imaging.
–Recently, Wicksline and Lanza
published a Circulation editorial
describing the coincident expansion
of nanoscale science and its role in
medicine. 1

3. - Molecular imaging has a primary goal
of enhancing the conspicuity of
microscopic pathologies by targeting the
molecular components that represent
the actual mechanisms of disease.
- Site targeted particles are intended to
enhance a selected biomarker that
otherwise might be impossible to
distinguish from surrounding normal
tissue.

4. Desired properties of targeted contrast agents:
•Long circulating half-life (hours)
•Selective binding to epitopes of interest
•Low background signal and prominent
contrast-to-noise enhancement
•Acceptable toxicity profile
•Ease of production and clinical use
•Applicability with standard commercially available
imaging modalities
•Promise for adjunctive therapeutic delivery

5. - Generally, targeting ligands are coupled
directly to the carriers and comprise
monoclonal antibodies, peptides, small
molecule peptidomimetics or aptamers
- In the past two decades, many
investigators have used monoclonal antibody
radio-labeled targeted imaging. However,
technical challenges including low S/N ratio
and poor spatial resolution severely limited
the clinical use of these investigations.

6. -Molecular imaging using MRI and
super paramgnetic iron oxide
nanoparticles attached to Her-2/neu
receptors for breast cancer imaging
was recently reported.
-http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?
cmd=Retrieve&db=PubMed&list_uids=12594741&dopt=Abstract
-A similar nanoparticle contrast
agent was used for imaging ICAM-1
in autoimmune encephalitis.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?
cmd=Retrieve&db=PubMed&list_uids=10683508&dopt=Abstract

7. -Imaging inflammatory markers in
atherosclerotic plaques using targeted
molecules involved in immune response
can be most useful in detection of
vulnerable plaques.
- Lanza, Wickline and colleagues reported
targeted antiproliferative drug delivery to
vascular smooth muscle cells with a
magnetic resonance imaging nanoparticle
contrast agent that can serve as a potential
therapy for restenosis.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12451012&dopt=Abstract

8. As featured in VPWatch of this
week, Murciano et al2
, have
provided evidence suggesting
that anti-ICAM molecules may
be used for immunotargeting
of anti-thrombotic drugs.

9. They hypothesized that blocking of a
highly expressed, pro-inflammatory
determinant that is up-regulated and
expressed on the endothelial lumen
may provide a powerful approach for
treatment and prophylaxis of vascular
inflammation and thrombosis, two key
components in the development,
progression and complication of the
atherosclerotic process

10. First, the authors cultured human endothelial
cells and demonstrated expression of modest
levels of ICAM-1.
HUVEC were incubated with 125
I-anti-ICAM or 125
I-IgG(1hr, 37 0
C)
and radioactivity determined in the surface fraction and cell lysates.

11. TNF-α stimulates anti-
ICAM binding but not
internalization of ICAM-
1. Of great therapeutic
importance, the largest
fraction of ICAM-1 is
exposed (not
internalized) on the
endothelial cells.

12. The immunospecificity of anti-ICAM or anti-
ICAM/tPA conjugate approached values of 250 and
50, respectively and, accordingly, control IgG
neither bound to the human endothelial cell in vitro
or accumulated in the lungs.

13. • The quantitative analysis
showed the potential binding
of up to 5-50 mg of anti-ICAM
in the human lung
vasculature, making it a very
attractive carrier when
compared to caveoli3
,
PECAM4
and ACE5
.

14. • The importance of these
findings is evidenced by the
known increased ICAM-1
endothelial expression in the
presence of cytokines,
oxidants, abnormal shear
stress, thrombin, etc.

15. • The authors stressed the fact that
ICAM-1 is not internalized,
phenomenon that occurs with other
potential therapeutic targets like
thrombomodulin or ACE. The possible
reason is that the carrier was larger
than 1µm and the endothelium is
known to internalize conjugates with a
mean diameter of only 100-200 nm.

16. The authors were also able to show that the
enzymatic (fibrinolytic) activity was retained in
the pulmonary vascular lumen.

17. Conclusion:
• Diagnostic imaging has the
capability of highlighting the actual
mechanisms of disease processes
using nanotechnology.
• MRI and CT are imaging
techniques potentially able to
track these molecular
phenomena.

18. Conclusion:
• ICAM offers an attractive target for
anti-thrombotic and anti-
inflammatory drug delivery in the
vascular beds.
• In vivo studies should provide
answers to many questions raised
by this exciting new therapeutic
approach.

19. • Which one of the following imaging
technologies is more practical to be
adopted for future clinical applications of
molecular imaging?
- MRI
- CT
- SPECT
- PET
- Ultrasound
Questions:

20. • Which one of the following molecules may
represent a better diagnostic target for
detection of vulnerable plaques?
– ICAM-1
– Ox-LDL
– LOX
– MMPs
– CRP
– Others
Questions:

21. References:
1. Wickline, S, Lanza, GM. Nanotechnology for Molecular Imaging and targeted therapy, Circulation 2003 Mar
4;107(8):1092-5
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12615782&dopt=Abstract
2. Murciano JC, Muro S, Koniaris L, Christofidou-Solomidou M, Harshaw DW, Albelda SM,
Granger DN, Cines DB, Muzykantov VR. ICAM-directed vascular immunotargeting of anti-
thrombotic agents to the endothelial luminal surface. Blood 2003 Jan 16;
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids
=12531816&dopt=Abstract
2. McIntosh DP, Tan XY, Oh P, Schnitzer JE. Targeting endothelium and its dynamic caveolae for
tissue-specific transcytosis in vivo: a pathway to overcome cell barriers to drug and gene delivery.
Proc Natl Acad Sci U S A 2002 Feb 19;99(4):1996-2001 .http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd
=Retrieve&db=PubMed&list_uids=11854497&dopt=Abstract,
3.Muzykantov VR, Christofidou-Solomidou M, Balyasnikova I, Harshaw DW, Schultz L, Fisher
AB, Albelda SM.
Streptavidin facilitates internalization and pulmonary targeting of an anti-endothelial cell
antibody (platelet-endothelial cell adhesion molecule 1): a strategy for vascular immunotargeting
of drugs http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?
cmd=Retrieve&db=PubMed&list_uids=10051650&dopt=Abstract, and
4.Danilov SM, Muzykantov VR, Martynov AV, Atochina EN, Sakharov IYu, Trakht IN, Smirnov
VN. Lung is the target organ for a monoclonal antibody to angiotensin-converting enzyme. http://
www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1846655&dopt=Abstract