Macromolecular agents composed of serum albumin or linear polymers have MRI contrast enhancement factors less than those predicted for rigid molecules of comparable size. MRI contrast agents based upon dendrimers obviate this deficiency. Terminal primary amines of dendrimers modified with appropriate chelating agents that effectively complex Gd(III) complexes are developed in our laboratories. These reagents possess a molar relaxivity of up to 6 times that of Gd(III)DTPA. Excellent conventional whole body MR imaging and 3D T-O-F MR angiograms have been obtained. Studies continue to thoroughly explore the utility of these agents. Evaluation of these macromolecular chelate conjugated dendrimer based Gd(III) MR contrast agents based on the PAMAM or the DAB classes of dendrimers have revealed that these agents can be tuned for various applications by tuning several fundamental criteria including: generation (MW & size), core elements (lipophilicity & charge), PEG conjugation, lysine co-administration (renal clearance), and conjugation to targetng vectors (molecular targeting). The PAMAM based agents have demonstrated imaging of murine tumor vasculature accurately at the 200 micron scale. The DAB class of agents has remarkably selective properties wherein reverse contrast images of 0.3 mm metastatic liver tumors could be detected and imaged and then their progession followed. We have also demonstrated that these agents can indeed be selectively targeted, not only by conjugation to antibodies, but to other vectors to deliver exceptionally high levels of Gd(III) into disseminated intraperitoneal ovarian cancer tumor. Current investigations include the assessment of the renal toxicity induced by chemotherapy whereby the MRI images of damaged kidney correlate with standard blood chemistries. Additionally, we are employing a range of PAMAM based agents to follow the effects of a variety of agents on tumor vasculature. Complementary to the MR contrast agents, both macromolecular and small molecular weight ESR spin-label agents have been prepared and are undergoing evaluation. In addition to these two types of imaging technology, protein based and dendrimer based CT contrast agents have also been prepared and are being evaluated in the appropriate model systems. The CT contrast agent based upon albumin conjugated to iopanoic acid continues to be evaluated in pre-clinical rodent and primate models for use in quantifying flow and dispersion of therapeutics being injected inter-cranially. This material is compared to a unique MRI albumin-based reagent prepared in these laboratories and preparations are underway to prepare this iodine-based reagent for use in clinical trials. Use of dendrimers to prepare a completely synthetic, and hence a more reproducible analog of the CT albumin reagent has been initiated. Characterization studies continue for this macromolecule to define the targeted products prior to any in vivo evaluation versus conventional low molecular weight CT contrast agents.
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