Brian James Grimmond

Conformation and Structure of Polymeric Contrast Agents for Medical Imaging

The structure of Gd-DTPA-polylysine, Gd-DOTA-polylysine, Gd-SCN-Bz-DOTA-polylysine, and Gd-DTPA-poly(glu:lys) was investigated with circular dichroism, gel permeation chromatography, low angle light scattering, and proton longitudinal relaxivity. Molecular modeling calculations were performed and predicted helical secondary structure for charged Gd-chelator residues, i.e., Gd-DTPA, when the DTPA conjugation levels reached 90% and higher. This helical secondary structure was observed with circular dichroism. The conformational transition from coiled to extended linear was observed also by gel permeation chromatography and by proton relaxivity measurements. The helical secondary structure was not observed when the chelator was changed to DOTA. The residue charge interactions were eliminated in this case since the Gd-DOTA complex had no net charge. For this construct, the gel permeation and relaxivity measurements indicated a coiled conformation. An extended linear conformation was regained when the chelator complex was changed to Gd-SCN-Bz-DOTA, which had a net negative charge. The functional aspects of these structures were investigated by MR imaging of an animal tumor model. The linear extended polymer constructs gave 10-fold higher tumor signals then the coiled-collapsed constructs, indicating a much higher degree of trans-endothelial transport in the tumors.

A Multimodal Contrast Agent for Preoperative MR Imaging and Intraoperative Tumor Margin Delineation

We have constructed a multimodal contrast agent suitable for near-infrared, NIR, fluorescent imaging as well as magnetic resonance imaging, MRI. This class of agents may be useful for preoperative tumor localization and tumor functional evaluation and for intraoperative delineation of tumor margins. We have covalently attached dyes of the cyanine family to a previously described polymeric contrast agent, Gd-DTPA-polylysine, of an extended, uncoiled conformation. The dual modality agent is as effective in imaging tumors by MRI as the parent compound provided that the dye loading on the polymer is such that it does not eliminate all the available free-lysine groups on the parent Gd-DTPA-polylysine polymers. NIR fluorescence from preclinical subcutaneous and orthotopic mammary gland tumors could be detected with a signal to background ratio of as high as 4.5 at 12 hours post agent injection at a dye dose of 125 nmole/kg. For intraoperative delineation of tumor margins, a wide-field illumination camera system was devised giving high signal to background NIR fluorescent images of surgically exposed orthotopic mammary gland tumors. Histologic microscopy confirmed the location of the dual modality agent at the boundary of the tumor with a margin distance of about 0.3 mm from labeled tumor cells.

Simultaneous monitoring of a bi-functional optical-MRI contrast agent using a hybrid DOT-MRI system

It is difficult to cross-validate the parameters measured by different modalities. Our in vivo small animal study is the first to validate a true multi-modality system (combined MRI-DOT system) with a true multi-modality contrast agent.

A multimodal contrast agent for simultaneous magnetic resonance and optical imaging of small animal

Our goal is to assess the feasibility of a bi-functional contrast agent that is intravenously injected to an R3230 induced small animal breast tumor model. The MR/optical contrast agent was produced by GE Global Research, NY, and it was available in one size, Dp20. We used a combined frequency domain diffuse optical tomography (DOT) and a 4T magnetic resonance (MR) scanner to simultaneously measure the kinetics of the contrast agent in vivo. Both systems detected the signal change in the tumor and the non-tumor region. MR measurements served as a gold standard to validate the optical kinetics. We present both MR and DOT dynamic curves as well as the reconstructed optical absorption map.