Macromolecular MRI contrast agents based upon dendrimers obviate many of the deficiencies of serum albumin or linear polymer based MRI contrast agents of comparable size. This is due to the iterative polymeric synthesis by which they are created that then promotes a controlled size and shape of the dendrimer that concomitantly then provides the means for reproducible chemistry that is key to the clinical translation of such agents. To create MRI contrast agents with dendrimers, the 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, the currently approved MRI contrast agent. Excellent conventional whole body MR imaging and 3D T-O-F MR angiograms have been obtained with PAMAM and polypropyleneimine or DAB dendrimer based agents. Past 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 dendrimer based 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. This study done in conjunction with an optical imaging agent runs in parallel with our creation of multi-modality dendrimer based imaging agents. 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 provided an additional level of sensitivity for the imaging of lymphatics and sentinel nodes that can be envisioned as being translated to an intraoperative scenario wherein MRI imaging and mapping would supplement real-time surgical intervention and excision of malignancy. While the chemistry established the ability to create such macromolecular agents, the imaging resulted in compromised targeting which defined that these agents require very careful systematic investigation combined with equally carefully defined characterization. Lastly, new chelation chemistry for conjugation of Gd(III) complexes to dendrimer has been prompted by the need to re-invent this filed moving it from aqueous chemistry back to organic phase solvents to enhance both characterization and consistency of yields. This chemistry has also evolved out of the need for specialized analogs of established bifunctional chelation agents to address the development of site-specific conjugation chemistry required for actively targeted dendrimer based imaging agents. In parallel to this effort, the very recent impact on NFS related Gd(III) toxicity of less than adequately stable MRI contrast agents prompted a complete halting of projects with an application of new directionality in the choice of bifunctional chelating agent at the heart of all of these studies. Thus, all ongoing projects were completed using the 1B4M-DTPA bifunctional chelate while all new projects were put on hold until adequate amounts of bifunctional DOTA became available through the synthesis efforts of the Section itself as opposed to purchase of this agent. While this effort was put into place over the past year, all of these projects have now moved over to use of a pre-complexation of the Gd(III) conjugation strategy using DOTA to eliminate a characterization complexity intended to simply translation of these agents into clinical use. Results from the studies to validate this transformation have revealed that not only can such a strategy be employed, but that far greater molar relaxivity can be achieved by this means. The exquisite advantages of the dendrimer based agents over low molecular weight agents continue to be very clearly demonstrated. In parallel to the development of dendrimer based agents, a long-term collaboration with NINDS investigators to develop a surrogate marker for CED of chemotherapeutic drugs continues to move forward with all of the above noted chemical modifications included to advance this technology into the clinic in the safest format possible. A US patent covering this technology was issued this year and is attracting considerable attention and interest that should contribute to translation of this technology into the clinic. Studies of MRI and other imaging modality agents in collaboration with the Molecular Imaging Program have unfortunately been effectively terminated due to a lack of cooperation and access to instrumentation residing therein what was to be a resource for all NCI researchers. However, collaboration with Radiology, CC, the PER Dept, CC, and NIMH , and extramural researchers have replaced the Molecular Imaging Program, NCI.
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