Editorial Slides VP Watch, March 19, 2003, Volume 3, Issue 11

Nanotechnology Promises Combined Molecular Imaging and Therapy for

Vulnerable Plaques

–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

- 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.

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

- 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.

-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

-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

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.

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

First, the authors cultured human endothelial cells and demonstrated expression of modest levels of ICAM-1.

HUVEC were incubated with 125I-anti-ICAM or 125I-IgG(1hr, 37 0C) and radioactivity determined in the surface fraction and cell lysates.

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.

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.

• 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.

• 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.

• 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.

The authors were also able to show that the enzymatic (fibrinolytic) activity was retained in

the pulmonary vascular lumen.

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.

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.

• 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:

• 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:

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=Abstract2. 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