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 chelated Gd(III) are developed in our laboratories. These reagents possess a molar relaxivity 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 and to thus simultaneously define their pharmacokinetics and dynamics. Results have established that these macromolecular chelate conjugated dendrimer based Gd(III) MR contrast agents can be tuned for various applications by adjusting tuning fundamental criteria: generation (MW and size), core elements (lipophilicity and charge), PEG conjugation, lysine co-administration (renal clearance), and conjugation to targetng 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 beenc 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) assessment of chemotherapy induced renal toxicity whereby the MRI images of damaged kidney correlate with standard blood chemistries; (2) imaging of the lymphatic system with particular attention to involvement of the lymph nodes relating to lymphoma; (3) imaging of breast cancer involvement with drainage to sentinal nodes for lymph node involvement diagnosis; and (4) effects of external beam radiation on the integrity of tumor vasculature. The first study has recently been extended to evaluate renal sepsis injury and demonstrated that this type of condition could be easily differentiate between reperfusion injury, and sepsis that was also predictive of time to death from sepsis in the animal model. The second and third studies very clearly demonstrated the exquisite advantages of the dendrimer based agents over small molecular weight agents. Draining sentinel nodes were clearly defined by MR imaging along with the involved lymphatic vessels in normal mice, transgenic mice that spontaneously develop breast cancer, and in xenograft tumor bearing mice. The fourth area of study determined the response of tumor vasculature to external beam radiation wherein a biological """"""""window"""""""" was opened permitting the measured leakage through tumor vessel fenestrations. The timc course kinetics of the opening and closing of this """"""""window"""""""" was also determined. Having established PK/PD baselines correlative with size and class of dendrimer, we now proceed to move forward from passively targeted macromolecular MRI contrast agents to the next phase of in our study to actively targeted dendrimer based imaging agents that may also be multi-modality imaging agents.
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