Sensitive Gadolinium-Loaded Apoferritin Probe Highlyby Targeting Neural Cell Adhesion Molecules with the Magnetic Resonance Visualization of Tumor Angiogenesis

Tumor vessel imaging could be useful in identifying angiogenic blood vessels as well as being a potential predictive marker of antiangiogenic treatment response. We recently reported the expression of the neural cell adhesion molecule (NCAM) in the immature and tumor endothelial cell (TEC) lining vessels of human carcinomas. Exploiting an in vivo model of human tumor angiogenesis obtained by implantation of TEC in Matrigel in severe combined immunodeficiency mice, we aimed to image angiogenesis by detecting the expression of NCAM with magnetic resonance imaging. The imaging procedure consisted of (a) targeting NCAMs with a biotinylated derivative of C3d peptide that is known to have high affinity for these epitopes and (b) delivery of a streptavidin/gadolinium (Gd)-loaded apoferritin 1:1 adduct at the biotinylated target sites. The remarkable relaxation enhancement ability of the Gd-loaded apoferritin system allowed the visualization of TEC both in vitro and in vivo when organized in microvessels connected to the mouse vasculature. Gd-loaded apoferritin displayed good in vivo stability and tolerability. The procedure reported herein may be easily extended to the magnetic resonance visualization of other epitopes suitably targeted by proper biotinylated vectors. (Cancer Res 2006; 66(18): 9196-201)

[1]  V. Berezin,et al.  NCAM mimetic peptides , 2007, Journal of Molecular Neuroscience.

[2]  L. Tei,et al.  Neural-cell adhesion molecule (NCAM) expression by immature and tumor-derived endothelial cells favors cell organization into capillary-like structures. , 2006, Experimental cell research.

[3]  Ralph Weissleder,et al.  Nanoparticle imaging of integrins on tumor cells. , 2006, Neoplasia.

[4]  S. Caruthers,et al.  Molecular imaging by MRI , 2006, Current cardiology reports.

[5]  A. Sherry,et al.  Catalytic effects of apoferritin interior surface residues on water proton exchange in lanthanide complexes. , 2006, Contrast Media & Molecular Imaging.

[6]  Klaas Nicolay,et al.  MR molecular imaging and fluorescence microscopy for identification of activated tumor endothelium using a bimodal lipidic nanoparticle , 2005, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[7]  Grace Hu,et al.  Molecular MR imaging of melanoma angiogenesis with ανβ3‐targeted paramagnetic nanoparticles , 2005, Magnetic resonance in medicine.

[8]  W. J. Oakes,et al.  Phase III clinical evaluation of gadoteridol injection: Experience in pediatric neuro-oncologic MR imaging , 2005, Pediatric Radiology.

[9]  J. Bulte,et al.  Magnetic resonance imaging of cell surface receptors using targeted contrast agents. , 2004, Current pharmaceutical biotechnology.

[10]  K. Nicolay,et al.  A liposomal system for contrast-enhanced magnetic resonance imaging of molecular targets. , 2004, Bioconjugate chemistry.

[11]  A. Blamire,et al.  MRI detection of early endothelial activation in brain inflammation , 2004, Magnetic resonance in medicine.

[12]  M. Neeman.  Preclinical MRI Experience in Imaging Angiogenesis , 2004, Cancer and Metastasis Reviews.

[13]  A. Kassner,et al.  Molecular Imaging of Angiogenesis in Nascent Vx-2 Rabbit Tumors Using a Novel ανβ3-targeted Nanoparticle and 1.5 Tesla Magnetic Resonance Imaging , 2003 .

[14]  G. Camussi,et al.  Altered angiogenesis and survival in human tumor‐derived endothelial cells , 2003, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[15]  P. Carmeliet.  Angiogenesis in health and disease , 2003, Nature Medicine.

[16]  V. Berezin,et al.  A Synthetic Peptide Ligand of Neural Cell Adhesion Molecule (NCAM), C3d, Promotes Neuritogenesis and Synaptogenesis and Modulates Presynaptic Function in Primary Cultures of Rat Hippocampal Neurons* , 2003, The Journal of Biological Chemistry.

[17]  Eliana Gianolio,et al.  Insights into the use of paramagnetic Gd(III) complexes in MR‐molecular imaging investigations , 2002, Journal of magnetic resonance imaging : JMRI.

[18]  V. Berezin,et al.  Increased intracellular calcium is required for neurite outgrowth induced by a synthetic peptide ligand of NCAM , 2002, FEBS letters.

[19]  Silvio Aime,et al.  Compartmentalization of a gadolinium complex in the apoferritin cavity: a route to obtain high relaxivity contrast agents for magnetic resonance imaging. , 2002, Angewandte Chemie.

[20]  R Weissleder,et al.  Molecular imaging. , 2009, Radiology.

[21]  A R Padhani,et al.  Challenges for imaging angiogenesis. , 2001, The British journal of radiology.

[22]  P. Carmeliet,et al.  Angiogenesis in cancer and other diseases , 2000, Nature.

[23]  V. Berezin,et al.  The neural cell adhesion molecule in synaptic plasticity and ageing , 2000, International Journal of Developmental Neuroscience.

[24]  L. Steinman,et al.  ICAM-1 expression in autoimmune encephalitis visualized using magnetic resonance imaging , 2000, Journal of Neuroimmunology.

[25]  R. Lauffer,et al.  Gadolinium(III) Chelates as MRI Contrast Agents: Structure, Dynamics, and Applications , 1999 .

[26]  Mathilde H. Lerche,et al.  Identification of a neuritogenic ligand of the neural cell adhesion molecule using a combinatorial library of synthetic peptides , 1999, Nature Biotechnology.

[27]  R. Lauffer,et al.  Gadolinium(III) Chelates as MRI Contrast Agents: Structure, Dynamics, and Applications. , 1999, Chemical reviews.

[28]  M. Bednarski,et al.  Detection of tumor angiogenesis in vivo by alphaVbeta3-targeted magnetic resonance imaging. , 1998, Nature medicine.

[29]  S. Eaton,et al.  Physicochemical properties, pharmacokinetics, and biodistribution of gadoteridol injection in rats and dogs. , 1995, Academic radiology.

[30]  Peter A. Rinck,et al.  Magnetic Resonance in Medicine , 1993 .

[31]  R. Soltys.  Summary of preclinical safety evaluation of gadoteridol injection. , 1992, Investigative radiology.

[32]  R. Crichton.  Proteins of iron storage and transport. , 1990, Advances in protein chemistry.

[33]  M. M. Bradford.  A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. , 1976, Analytical biochemistry.