Two-compartment pharmacokinetic modeling of targeted molecular MRI contrast agents

Introduction Molecular MRI allows the specific detection of biomolecules that are upregulated during disease. To this extent, contrast agents (CAs) are used that home to the targeted biomolecules via high affinity ligands coupled to the CA. Activated endothelial cells in tumor angiogenesis provide well suited disease markers, which are easily accessible for circulating CAs. Several studies have already demonstrated the MRI responses induced by these targeted particles in terms of increases in signal intensity 2 or relaxation rates. However, the dynamic homing behavior and pharmacokinetics of targeted CA particles are largely unknown. Moreover, the intrinsic low molecular sensitivity of MRI requires the use of relatively large CAs, which may poorly penetrate deep tumor tissue. The goal of this work was to develop a pharmacokinetic model to describe the dynamic behavior of the previously developed cNGR-labeled paramagnetic quantum dots (cNGR-pQDs). The cyclic tripeptide ligand cNGR was shown to home specifically to the transmembrane protein CD13, which is upregulated on endothelial cells of angiogenic tumor vessels. The model also provides information on whether the CA distributes throughout the entire tumor or not. This is important since the highest CA induced changes were always observed in the tumor rim. Although this area is known to have the highest level of angiogenic activity, the strong effects in the rim may also be related to the high interstitial pressures in the tumor, thereby preventing CA-delivery in the deeper tumor tissue.