Current Pharmaceutical Biotechnology, Vol. 5, No. 6, 2004
Contents
MR
Contrast Agents for Molecular and Cellular Imaging
Guest
Editor: Jeff W.M. Bulte
Magnetic
Resonance Imaging of Cell Surface Receptors Using Targeted Contrast Agents Pp. 485-494
Dmitri
Artemov, Zaver M. Bhujwalla and Jeff W.M. Bulte
Novel
Paramagnetic Contrast Agents for Molecular Imaging and Targeted Drug Delivery Pp. 495-507
Gregory
M. Lanza, Patrick Winter, Shelton Caruthers, Anne Schmeider, Kathy Crowder,
Anne Morawski, Huiying Zhang, Michael J. Scott and Samuel A. Wickline
Targeting
Cells with MR Imaging Probes Based on Paramagnetic Gd(III) Chelates Pp. 509-518
S.
Aime, A. Barge, C. Cabella, S. Geninatti Crich and E. Gianolio
Activated
MR Contrast Agents Pp. 519-528
Mark
P. Lowe
Manganese
Enhanced Magnetic Resonance Imaging
Pp. 529-537
Jung
Hee Lee and Alan P. Koretsky
Dendrimer-Based
Nanosized MRI Contrast Agents Pp.
539-549
Hisataka
Kobayashi and Martin W. Brechbiel
A
Non-Invasive Approach to Detecting Organ Rejection by MRI: Monitoring the
Accumulation of Immune Cells At the Transplanted Organ Pp. 551-566
Chien
Ho and T. Kevin Hitchens
Monitoring
Cell Therapy Using Iron Oxide MR Contrast Agents Pp. 567-584
Jeff W.M. Bulte and Dara L. Kraitchman
Abstracts
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Magnetic Resonance Imaging of Cell
Surface Receptors Using Targeted Contrast Agents
Dmitri Artemov, Zaver M. Bhujwalla, and Jeff W.M. Bulte
Over the past decade MR (magnetic resonance) imaging has emerged as one of the major modalities for noninvasive functional imaging. Recent advances in the development of targeted MR contrast agents have added significantly to the capabilities of MR imaging. In particular, the use of targeted contrast agents to report on the expression of cell surface receptors, combined with the functional capabilities of MR imaging, together provide unique opportunities to understand receptor-mediated pathways. In this article we have reviewed current MRI strategies used to visualize receptor expression, the potential advantages and drawbacks of these strategies, and novel areas of focus for the future.
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Novel Paramagnetic Contrast Agents for
Molecular Imaging and Targeted Drug Delivery
Gregory
M. Lanza, Patrick Winter, Shelton Caruthers, Anne Schmeider, Kathy Crowder,
Anne Morawski, Huiying Zhang, Michael J. Scott and Samuel A. Wickline
Molecular biology and genomic sciences are revealing the early biological signatures for many diseases. In response, the Molecular Imaging community is rapidly developing contrast agents to visualize the nascent pathological changes and to concomitantly deliver treatment directly to the site of disease. The evaluation, development and use of these new agents require a complementary understanding of contrast chemistry and imaging techniques. The fundamental issues surrounding magnetic contrast agent development, rational drug delivery, MR molecular imaging, and their interdependence are elucidated.
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Targeting Cells with MR Imaging Probes
Based on Paramagnetic Gd(III) Chelates
S. Aime, A. Barge, C. Cabella, S. Geninatti Crich and E.
Gianolio
The low sensitivity is the major disadvantage of MRI as compared to PET. Therefore, amplification strategies are necessary for specific pathway labeling.
This survey is aimed at exploring different routes to the entrapment of Gd(III) chelates in various type of cells at amounts sufficiently large to allow MRI visualization. Namely, the obtained results have been summarized in terms of internalization via i) pinocytosis; ii) phagocytosis; iii) receptors; iv) receptor mediated endocytosis; v) transporters; vi) transmembrane carrier peptides.
MRI visualization of cells appears possible when the number of internalized Gd(III) chelates is of the order of 107-108/cell.
Pinocytosis shows to be particularly useful for labeling cells that can be incubated for several hours in the presence of high concentrations of Gd-agent. This approach appears very effective for labeling stem cells. Nanoparticles filled with Gd-chelates can be used for an efficient loading of cells endowed with a good phagocytic activity. Entrapment via receptors most often results in receptor mediated endocytosis. Suitably functionalized monomeric and multimeric Gd-chelates can be considered for being internalized by this route as well as supramolecular systems such as those formed between Avidin and biotinylated Gd-complexes. Exploitation of up-regulated transporters of nutrients in tumor cells appears to be a promising route for their differentiation from healthy cells. Finally, properly designed systems entering the cells by means of penetrin-like peptides deserve great attention.
[Back to
top] Activated MR Contrast Agents
Mark
P. Lowe
The relative non-specificity of the first generation MR contrast agents has meant that a new approach to their design is required. This review focuses on a new class of more specific or functional agents. These are the so-called “activated”, “smart” or “responsive” contrast agents. The relaxivity of an activated contrast agent is responsive to (or can be modulated by) a particular in vivo stimulus such as a change in biological environment or activity. More specifically, a “switching on” of contrast in response to an event such as a change in physiological pH, metal ion concentration, enzyme activity or partial pressure of oxygen is sought. The current generation of activated MR contrast agents is discussed herein.
[Back to
top] Manganese Enhanced Magnetic Resonance Imaging
Jung Hee Lee and Alan P. Koretsky
Manganese is an essential metal that participates as a co-factor in a number of critical biological functions such as electron transport, detoxification of free radicals, and synthesis of neurotransmitters. Like other heavy metals, high concentrations of manganese are toxic. For example, chronic overexposure to manganese leads to movement disorders. In order to maintain this balance between being an essential participant in enzyme function and being a toxic heavy metal, a rich biology has evolved to transport and store manganese. Paramagnetic forms of manganese ions are potent MRI relaxation agents. Indeed, Mn2+ was the first contrast agent proposed for use in MRI. Recently, there is renewed interest in combining the strong MRI relaxation effects of Mn2+ with its unique biology in order to expand the range of information that can be measured by MRI. Manganese Enhanced MRI is being developed to give unique tissue contrast, assess tissue viability, act as a surrogate marker of calcium influx into cells and trace neuronal connections. In this article we review recent work and point out prospects for the future uses of manganese enhanced MRI.
[Back to
top] Dendrimer-Based Nanosized MRI Contrast Agents
Hisataka Kobayashi and Martin W. Brechbiel
Paramagnetic metals can induce T1 shortening by interaction with free water molecules. Two metal ions, Gadolinium and Manganese, are currently available for human use. Gadolinium-based MRI contrast agents (CAs) can operate using a ~100-fold lower concentration of Gadolinium ions in comparison to the necessary concentration of Iodine atoms employed in CT imaging in the tissues. Therefore, numerous macromolecular MRI CAs prepared employing relatively simple chemistry are readily available that can provide sufficient enhancement for multiple applications. Herein, we describe the synthesis, characteristics, and potential applications of dendrimer-based macromolecular MRI CAs in our recently reported libraries. This entire series of dendrimer-based macromolecular MRI CAs have a spherical shape and possess similar surface charges. Changes in molecular size altered the route of excretion. Smaller sized contrast agents, of less than 60 kD molecular weight, were excreted through the kidney resulting in these agents being potentially suitable as functional renal contrast agents. Less hydrophilic and larger sized contrast agents were found better suited for use as blood pool contrast agents. Hydrophobic variants of CAs formed with polypropylenimine diaminobutane dendrimer cores quickly accumulated in the liver and can function as liver contrast agents. Larger hydrophilic agents are also useful for lymphatic imaging. Finally, contrast agents conjugated with either monoclonal antibodies or with avidin are able to function as tumor-specific contrast agents and might also be employed as therapeutic drugs for either gadolinium neutron capture therapy or in conjunction with radioimmunotherapy.
[Back to
top] A Non-Invasive Approach to Detecting Organ Rejection by MRI:
Monitoring the Accumulation of Immune Cells At the Transplanted Organ
Chien
Ho and T. Kevin Hitchens
Organ transplantation is the generally preferred medical procedure of treatment for patients with end-stage organ failure. The immunological reaction of rejection is a major cause of functional failure in transplant patients. The current “gold standard” for detecting or confirming graft rejection following solid organ transplantation requires biopsy samples in order to detect immune cell (e.g., T-cells, macrophages, etc.) infiltration into the graft and other pathological changes. This procedure is not only invasive, having associated risks, but is also prone to sampling errors that can yield false negative results. To circumvent the need for biopsies, we are developing magnetic resonance imaging (MRI) techniques to monitor the accumulation of immune cells at the transplanted organ as a means to detect graft rejection. By labeling immune cells with an MRI contrast agent, dextran-coated ultrasmall superparamagnetic iron oxide (USPIO) particles, we can monitor the accumulation of these labeled immune cells at the rejecting graft as a non-invasive method to detect graft rejection. Cells can be labeled ex vivo and then infused into the animal, or MRI contrast agents can be introduced directly into the animal in vivo. Our results show excellent correlation among the MRI signal intensity due to the USPIO-labeled macrophages at the rejecting graft, immuno-staining for macrophages, histo-pathology for graft rejection, and the iron staining of tissue samples. In this article, we shall give a summary of our progress from detecting single immune cells in vitro to monitoring the accumulation of immune cells in vivo at the transplanted kidneys, hearts, and lungs in our rat models for organ transplantation by MRI.
[Back to
top] Monitoring Cell Therapy Using Iron Oxide MR Contrast Agents
Jeff W.M. Bulte and Dara L. Kraitchman
Given the remarkable progress that has
recently been obtained in animal studies, the clinical use of stem and
progenitor cells to correct or replace defective cell populations may soon
become a reality. In order to develop effective cell therapies, the location
and distribution of these cells must be determined in a non-invasive manner.
Magnetic resonance (MR) tracking of magnetically labeled cells following
transplantation or transfusion may fulfill this requirement. Indeed, a series
of recent studies indicate that MRI cell tracking has great potential for
further evaluation and optimization of cell therapy. Due to its
biocompatibility and strong effects on T2(*) relaxation, iron oxide
nanoparticles appear to be the contrast agent of choice, and several methods
now exist to shuttle sufficient amount of these compounds into cells. Most of
the tracking work has been carried out in disease models of the central nervous
system, but, recently, the infarcted heart has also received attention. With
its excellent spatial resolution and the ability to track labeled cells over
prolonged periods of time, MR monitoring of cell therapy is likely to become an
important technique in the foreseeable future.