Pharmacokinetics of contrast agents targeted to the tumor vasculature in molecular magnetic resonance imaging.
Molecular magnetic resonance imaging (MRI) is increasingly used to investigate tumor angiogenic activity non-invasively. However, the pharmacokinetic behavior and tumor penetration of the often large contrast agent particles is thus far unknown. Here, pharmacokinetic analysis of cyclic asparagine-glycine-arginine (cNGR) labeled paramagnetic quantum dots (pQDs) was developed to quantify the contrast agent's homing efficacy to activated endothelial cells of angiogenic tumor vessels using dynamic contrast-enhanced (DCE) MRI. cNGR homes to CD13, an overexpressed aminopeptidase on angiogenic tumor endothelial cells. First, a two-compartment pharmacokinetic model, comprising the blood space and endothelial cell surface, was compared with a three-compartment model additionally including the extravascular-extracellular component. The resulting extravasation parameter was irrelevantly small and was therefore neglected. Next, the association constant K(a), the dissociation constant k(d) and the fractional plasma volume v(P) were determined from the time-series data using the two-compartment model. Magnitude and spatial distribution of the parameters were compared for cNGR-labeled and unlabeled pQDs. The tumor area with significant K(a) values was approximately twice as large for cNGR-pQDs compared with unlabeled pQDs (p < 0.05), indicating more contrast agent binding for cNGR-pQDs. Using cNGR-pQDs, a two-fold larger area with significant K(a) was also found for the angiogenic tumor rim compared with tumor core (p < 0.05). It was furthermore found that both contrast agents perfused the tumor at all depths, thereby providing unequivocal evidence that rim/core differences can indeed be ascribed to stronger angiogenic activity in the rim. Summarizing, molecular DCE-MRI with pharmacokinetic modeling provides unique information on contrast agent delivery and angiogenic activity in tumors.
Oostendorp
Marlies
M
Department of Radiology, Maastricht University Medical Centre (MUMC), Maastricht, The Netherlands.
Douma
Kim
K
Hackeng
Tilman M
TM
van Zandvoort
Marc A M J
MA
Post
Mark J
MJ
Backes
Walter H
WH
D000818:Animals; D045744:Cell Line, Tumor; D003287:Contrast Media / Q000493:pharmacokinetics*; D006207:Half-Life; D006801:Humans; D007700:Kinetics; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008297:Male; D051379:Mice; D018613:Microscopy, Confocal; D057054:Molecular Imaging / Q000379:methods*; D009369:Neoplasms / Q000098:blood supply*; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D009928:Organ Specificity; D010456:Peptides, Cyclic / Q000493:pharmacokinetics*; D017785:Photons; D045663:Quantum Dots; D013997:Time Factors; D023041:Xenograft Model Antitumor Assays
D003287:Contrast Media; D010456:Peptides, Cyclic; C551526:cyclo(aspargyl-glycyl-arginyl)