Macromolecular MRI contrast agents based upon dendrimers obviate the deficiencies of serum albumin or linear polymer based MRI contrast agents of comparable size. Terminal primary amines of dendrimers modified with chelated Gd(III) are developed in our laboratories. These reagents possess a molar relaxivity 6 times that of Magnevist. Excellent conventional whole body MR imaging and 3D T-O-F MR angiograms have been obtained. Studies continue to define the utility and pharmacokinetics and dynamics of these agents. Results have established that macromolecular chelate conjugated dendrimer based Gd(III) MR contrast agents can be tuned for various applications by adjusting fundamental criteria: generation (MW & size), core elements (lipophilicity & charge), PEG conjugation, lysine co-administration (renal clearance), and conjugation to targeting vectors (molecular targeting). PAMAM based agents have imaged murine tumor vasculature accurately at the 200 micron scale. DAB based agents have selective properties wherein reverse contrast images of 0.3 mm metastatic liver tumors were detected. These agents have also been selectively targeted, not only by conjugation to antibodies, but by other vectors, such as avidin to deliver exceptionally high levels of Gd(III) into disseminated intraperitoneal ovarian cancer tumor. Recent results include: (1) the incorporation of a NIR optical imaging dye into the MRI agent to add an enhanced level of sensitivity to complement the resolution of the MRI imaging; (2) creation of dendrimer based MRI agents that may be conjugated to targeting moieties such as monoclonal antibodies or even peptides; and (3) dendrimer based MRI imaging agents that target angiogenesis markers. Thus, we are now proceeding forward from passively targeted macromolecular MRI contrast agents to the creation of actively targeted dendrimer based imaging agents that may also be multi-modality imaging agents, e.g. optical and MR imaging within the auspices of an actively targeted cell surface antigen. Another strategy being pursued in parallel is the site-specific 1:1 conjugation of the dendrimer elements with antibody fragments. Active targeting is also being actively pursued via multi-valence incorporation of various peptide elements, RGD for example. Lastly, recent achievements include the creation of multi-modality imaging agent that possesses both chelated Gd(III) for MRI imaging but also incorporates molecules of an infrared dye. This combination permits the combination of the structural resolution of MRI imaging with the sensitivity optical imaging. Current studies of this agent are proceeding in the evaluation of sentinel node imaging in those models established in collaboration with the Molecular Imaging Program. The exquisite advantages of the dendrimer based agents over small molecular weight agents continues to be very clearly demonstrated.

Agency
National Institute of Health (NIH)
Institute
Division of Clinical Sciences - NCI (NCI)
Type
Intramural Research (Z01)
Project #
1Z01SC010051-11
Application #
7331429
Study Section
(ROB)
Project Start
Project End
Budget Start
Budget End
Support Year
11
Fiscal Year
2006
Total Cost
Indirect Cost
Name
Clinical Sciences
Department
Type
DUNS #
City
State
Country
United States
Zip Code
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