Modulation of the pharmacokinetics of macromolecular contrast material by avidin chase: MRI, optical, and inductively coupled plasma mass spectrometry tracking of triply labeled albumin

The goal of this work was to develop an MRI method for mapping the clearance of interstitial macromolecular plasma proteins after their extravasation from permeable blood vessels. To that end, a well-defined window of exposure to elevated blood levels was generated by inducing rapid clearance of macromolecular contrast material from the blood. Experimental removal of the intravascular component allowed subsequent tracking of clearance from the interstitial compartment in the absence of further contrast extravasation. The contrast material was based on albumin triply labeled with biotin, fluorescent tag, and Gd-DTPA, allowing optical, inductively coupled plasma mass spectrometry (ICP-MS) and MRI detection. The biotin tag was used here for in vivo chasing of the contrast material from the blood by intravenous administration of avidin. Upon administration of avidin the contrast material disappeared from the blood vessels and was cleared by the liver and spleen as detected by MRI, fluorescence of blood samples and histological sections, and by ICP-MS. Nonbiotinylated fluorescent albumin was not affected by administration of avidin. Contrast material that extravasated from leaky blood vessels in a VEGF overexpressing tumor, prior to administration of avidin, was not cleared by the addition of avidin and showed continued interstitial convection. Thus, avidin-chase provides an effective tool for in vivo manipulation of the arterial input function by providing experimental control over the rate of clearance of the contrast material from the circulation. (C) 2003 Wiley-Liss, Inc.