Macromolecular magnetic resonance imaging (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 these agents are created. This iterative synthesis promotes a controlled size and shape of the dendrimer which 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 laboratory. These reagents possess a molar relaxivity 6 times that of Magnevist, the currently approved MRI contrast agent. Excellent conventional whole-body magnetic resonance imaging and three-dimensional (3D) time-of-flight (TOF) magnetic resonance angiograms have been obtained with polyamidoamine (PAMAM) and polypropyleneimine or DAB dendrimer-based agents. Past results have established that macromolecular chelate-conjugated dendrimer-based Gd(III) magnetic resonance contrast agents can be tuned for various applications by adjusting fundamental criteria: generation (molecular weight and size), core elements (lipophilicity and 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. Our studies continue to define the fundamental properties of these agents as well as their potential clinical utility, and the pharmacokinetics and dynamics of these agents. 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 was done in conjunction with an optical imaging agent run in parallel with our creation of multi-modality dendrimer-based imaging agents. The incorporation of a near infrared (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. Carry forward with the active targeting aspect beyond avidin, which has only proof in principle value and no clinical import, targeting alpha v beta 3 with RGD peptide-conjugated dendrimer with an optical imaging agent was also investigated to image tumor neovasculature and angiogenesis. 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. These studies also formed the basis for translation of these agents towards a clinical trial aimed at imaging the lymphatics in collaboration with the Molecular Imaging Program and Children's Hospital in Boston, MA. Lastly, new chelation chemistry for conjugation of Gd(III) complexes to dendrimer has been prompted by the need to re-invent this field, 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 with 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, these projects are also moving towards a pre-complexation of the Gd(III) conjugation strategy to eliminate a characterization complexity intended to simply translation of these agents into clinical use. In parallel with 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. Current studies of these agents 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 low molecular weight agents continue to be very clearly demonstrated.
NIH ExPorter
NIH ExPorter