Magnetic resonance pharmacoangiography to detect and predict chemotherapy delivery to solid tumors.
Detection and prediction of drug delivery to the tumor interstitium are of critical importance in cancer chemotherapy. Prediction of drug delivery derived from standard pharmacokinetic models is frequently inadequate because of the complex nature of tumor blood flow and the microenvironment. Although drug concentrations can be directly sampled with microdialysis or in biopsy samples, we currently lack methods capable of detecting and/or predicting drug delivery to tumors noninvasively. In this study, we describe a novel magnetic resonance (MR) technique to directly detect the drug, and we present the correlation between delivery of drug and the delivery of MR contrast agents to the tumor. Experiments were performed with tumor xenografts in severe combined immunodeficient mice. Three-dimensional maps of the drug distribution within the tumors were obtained with 13C spectroscopic MR imaging with a spatial resolution of 2 x 2 x 2 mm, using signals of the 13C-labeled anticancer agent phenylacetate. Three-dimensional maps of uptake of gadolinium-diethylenetriaminepentaacetic acid (GdDTPA) contrast agent were obtained for the same tumors using dynamic MR imaging. Experimental data were analyzed for correlation between delivery of the drug and the contrast. Histological analysis was performed for excised tumors. Experimental data demonstrated a significant spatial correlation (r = 0.59 with P < 0.001) between the parameter representing delivery of the contrast to tumor interstitium, determined from the kinetic curves of GdDTPA, and integral tissue drug concentrations for two different tumor models. The method is designed to probe extravasation of the drug molecules from the bloodstream into the tumor interstitium. Although therapeutic efficiency of the drug will also depend upon drug retention in the tumor and the ability of the molecules to cross cellular membranes, inefficient drug transfer from plasma to tissue can be a major impediment in achieving effective tumor chemotherapy. The results of this study demonstrate that the uptake kinetics of a low molecular weight MR contrast agent can be used to predict delivery of drug molecules of similar size to the interstitium of solid tumors.
Artemov
D
D
Department of Radiology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. dmitri@mri.jhu.edu
Solaiyappan
M
M
Bhujwalla
Z M
ZM
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000493:pharmacokinetics* / Q000494:pharmacology; D001943:Breast Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000378:metabolism*; D002247:Carbon Isotopes; D003287:Contrast Media / Q000493:pharmacokinetics; D016903:Drug Monitoring / Q000379:methods; D005240:Feasibility Studies; D005260:Female; D019786:Gadolinium DTPA / Q000493:pharmacokinetics; D006801:Humans; D018810:Magnetic Resonance Angiography / Q000379:methods*; D008297:Male; D051379:Mice; D016513:Mice, SCID; D010648:Phenylacetates / Q000493:pharmacokinetics; D011471:Prostatic Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
D000964:Antimetabolites, Antineoplastic; D002247:Carbon Isotopes; D003287:Contrast Media; D010648:Phenylacetates; C025136:phenylacetic acid; D019786:Gadolinium DTPA