Novel Technologies at CMIR

The long-term goal of the CMIR is to overcome current boundaries of conventional diagnostic imaging and develop techniques to image targets at subcellular and molecular levels in vivo. CMIR researchers have developed a number of key technologies, reagents and techniques for imaging as summarized below.

Nanoparticle Chemistry and Bioconjugation

CMIR has long been a pioneer in the research and development of iron oxide based contrast agents. These materials are valuable probes to study specific molecular processes in animal research. Research at CMIR has helped pave the way for the ongoing clinical development and commercial use of this important class of contrast agents.

Weissleder R. Method of Studying Biological Tissue using Monocrystalline Particles. US patent #5,492,814.

Weissleder, R., et al., Superparamagnetic iron oxide: enhanced detection of focal splenic tumors with MR imaging. Radiology, 1988. 169(2): p. 399-403.

Weissleder, R., et al., Ultrasmall superparamagnetic iron oxide: characterization of a new class of contrast agents for MR imaging. Radiology, 1990. 175(2): p. 489-93.

Reimer, P., et al., Receptor imaging: application to MR imaging of liver cancer. Radiology, 1990. 177(3): p. 729-34.

Shen, T., et al., Monocrystalline iron oxide nanocompounds (MION): physicochemical properties. Magn Reson Med, 1993. 29(5): p. 599-604.

Shen, T.T., et al., Magnetically labeled secretin retains receptor affinity to pancreas acinar cells. Bioconjug Chem, 1996. 7(3): p. 311-6.

Cell Labeling and Tracking In Vivo

The ability to label and track cells is an important capability for research in transplantation medicine, immunology and gene therapy. Magnetic, fluorescent and radioactive cell labeling techniques are used at CMIR to gather data on this important problem. CMIR has pioneered the development of materials that permit the labeling of cells for tracking by high resolution MRI.

Josephson L, Tung CH, Moore A, Weissleder R. High efficiency intracellular magnetic labeling is possible with novel superparamagnetic Tat peptide conjugates. Bioconjugate Chemistry, 1999;10:186-191

Lewin M, Carlesso N, Tung C, Tang X, Cory D, Scadden D, Weissleder R. Tat peptide derivatized magnetic nanoparticles allow in vivo tracking and recovery of progenitor cells. Nature Biotech, 2000;18:410-414.

Viral Labeling and Tracking In Vivo

To support gene therapy research, techniques to image DNA, the expression of therapeutic genes, and the fate of gene therapy vectors are needed. Each of these techniques is a major area of research at CMIR. CMIR was the first to develop method to track the in vivo distribution of herpes simplex virions during gene therapy. These studies have resulted in important information regarding the kinetics of viral distribution and optimized administration routes.

Schellingerhout D, Bogdanov A, Marecos E, Spear M, Breakefield X, Weissleder R. Mapping the in vivo distribution of Herpes simplex virions. Human Gene Therapy, 1998; 9:1543-1549.

Schellingerhout D, Rainov NG, Breakefield XO, Weissleder R. Quantitation of HSV mass distribution in a rodent brain tumor model. Gene therapy, 2000; 7:1648-1655.

DNA Labeling and Imaging

As part of CMIR’s effort to support gene therapy research, investigators have developed a method to directly label double stranded DNA with radioactive tracers. This permit an understanding of the rates of movement and eventual disposition of of DNA used gene therapy.

Bogdanov A, Tung CH, Bredow S, Weissleder R. DNA binding chelates for non-viral gene delivery imaging. Gene Therapy, 2000, in press.

Bogdanov A, Tung CH, Weissleder R. Non-invasive imaging of nucleic acid vectors. US patent application filed 6/3/99.

Bogdanov A, Tung CH, Weissleder R. Non-invasive imaging of nucleic acid vectors. US patent application filed 6/3/99.

In Vivo MR Imaging of Gene Expression (Gene Transfer)

We have demonstrated that transgene expression can be detected by MR imaging using mutated internalizing receptors or tyrosinase mutants. Some of this technology is now being explored to image endogenous gene expression.

Weissleder R, Moore A, Mahmood U, Bhorade R, Benveniste H, Chiocca E Basilion JB. in vivo MR imaging of transgene expression. Nature Medicine, 2000; 6:351-355.

Weissleder R, Simonova M, Bogdanova A, Bredow S, Enochs WS, Bogdanov A. MR imaging and scintigraphy of gene expression through melanin induction. Radiology, 1997; 204:425-429.

Simonova, M., et al., Tyrosinase mutants are capable of prodrug activation in transfected nonmelanotic cells. Cancer Res, 2000. 60(23): p. 6656-62.

Bogdanov A, Simonova M, Weissleder R. Engineering membrane proteins for nuclear medicine: applications for gene therapy and cell tracking. Q J Nucl. Med, 2000; 44 (3):224-235.

Bogdanov A, Weissleder R, Simonova M. Compositions and methods for imaging gene expression. US patent application (1/31/98) USSN 09/015,366.

Weissleder R, Basilion J, Chiocca N. in vivo imaging of gene expression. US patent application filed 4/23/99.

Fluorescence Sensing of Enzyme Activity

Investigators at CMIR have pioneered and patented new types of optical probes, those that are activated to fluoresce in the near infrared portion of spectrum by specific enzymes. These smart optical imaging probes have been used to detect and quantitate a variety of enzymes in vivo. We have also developed tomographic imaging systems to detect the de-quenching of protease probes in vivo.

Weissleder R, Tung CH, Mahmood U, Bogdanov A. in vivo imaging of enzyme activity with amplifiable near infrared fluorescent probes. Nature Biotechnology, 1999; 17:375-378.

Tung CH, Bredow S, Mahmood U, Weissleder R. Potential cathepsin-D sensitive near infrared fluorescent probe for in vivo imaging. Bioconjugate Chem, 1999; 10;892-896

Bremer C, Tung, Weissleder R. in vivo molecular target assessment of MMP-2 inhibition. Nature Medicine, 2001; in press

Weissleder R, Tung C, Mahmood U, Josephson L, Bogdanov A. Intramolecularly quenched near infrared fluorescent probes. US patent 6,083,486

Polymers for Imaging and Drug Delivery

A number of different non-immunogenic drug delivery systems and gels have been pioneered in our laboratories over the years. The commercial nature of this area has led to an emphasis on patenting our advances.

Bogdanov, A.A., et al., An adduct of cis-diamminedichloroplatinum(II) and poly(ethylene glycol)poly(L-lysine)-succinate: synthesis and cytotoxic properties. Bioconjug Chem, 1996. 7(1): p. 144-9.

Bogdanov, A., et al., A long-circulating co-polymer in “passive targeting” to solid tumors. J Drug Target, 1997. 4(5): p. 321-30.

Weissleder R, Bogdanov A. Hydrogel Compositions and Methods of Use. US patent 5,514,379.

Bogdanov A, Callahan R, Weissleder R, Brady TJ. Blood pool imaging composition and method of its use. US patent #5,605,672.

Bogdanov A, Weissleder, Brady TJ. Graft Co-Polymer adducts of platinum (II) compounds. US patent, #5,871,710

Lymph Node Imaging and Detection of Nodal Metastases

CMIR has been at the forefront of development of lymphotrophic MR contrast agents and drug delivery systems. Monocrystyalline iron oxides nanoparticles (MION), a preparation developed at CMIR, has been used for experimental lymph node imaging in small animals..

Harika L, Weissleder R, Poss K, Zimmer C, Papisov M, Brady TJ. MR lymphography with a lymphotropic T1-type MR contrast agent: GdDTPA-PGM. Magn Reson Med, 1995; 33:88-92.

Weissleder R, Elizondo G, Wittenberg J, Lee A, Josephson L, Brady T. Ultrasmall superparamagnetic iron oxide: An intravenous contrast agent for assessing lymph nodes with MR imaging. Radiology, 1990; 175: 494-498.

Weissleder R, Elizondo G, Wittenberg J, Rabito CA, Bengele H, Josephson L. Ultrasmall superparamagnetic iron oxide: Characterization of a new class of contrast agents for MR imaging. Radiology, 1990; 175: 489-493.

Harisinghani, M. G., Barentsz, J., Hahn, P. F., Deserno, W. M., Tabatabaei, S., van de Kaa, C. H., de la Rosette, J., and Weissleder, R. Noninvasive detection of clinically occult lymph-node metastases in prostate cancer. N Engl J Med, 348: 2491-9, 2003.

Harisinghani MG, Weissleder R Sensitive, noninvasive detection of lymph node metastases.. PLoS Med, 1(3): e66, 2004.

Key Technologies Under Development at CMIR

Optical Imaging Technology

Optical imaging technology under development includes the synthesis of new dyes, the synthesis of new activatable dye conjugates, and the design and upgrading of devices for detecting fluorescence in vivo.

Magnetic Nanoparticles as Biosensors

We are developing a new generation of nanoparticles that will serve as biosensors for the detection of a variety different types of analytes.

Stem Cells

Using CMIR’s cell labeling technology we are now purifying specific classes of cells, labeling them and tracking them in vivo to derive answers to crucial questions in cellular immunology, development biology and neurosciences.

Chemical Biology

We are using different tools to fast forward the development of novel imaging ligands in collaboration with the Broad Institute.

Bioinformatic Tools

A new information platform - Molecular Imaging Portal (MIPortalR) allows for the integration of imaging with clinical and molecular (genomic, proteomic) datasets and provides capabilities for cross-modular information management.

We are also developing advanced visualization and quantitation tools for biological imaging.