Application of a Macromolecular Contrast Agent for Detection of Alterations of Tumor Vessel Permeability Induced by Radiation

Abstract

Permeability of tumor vasculature can be a major barrier to successful drug delivery, particularly for high molecular weight agents such as monoclonal antibodies and their diagnostic or therapeutic conjugates. In this study, changes in permeability of SCCVII tumor vessels after radiation treatment were evaluated by dynamic magnetic resonance imaging as a function of time after irradiation using a generation-8 polyamidoamine dendrimer (G8-Gd-D)-based magnetic resonance imaging contrast agent shown previously to be confined to tumor blood vessels. Tumor irradiation consisted of either single doses (2-15 Gy) or various daily fractionated doses (5 days). A single radiation dose of 15 Gy resulted in significant transient image enhancement of the tumor tissue with a maximum occurring between 7 and 24 hours after radiation treatment. No observable enhancement was recorded for fractionated radiation doses. Use of dynamic magnetic resonance imaging coupled with G8-Gd-D provides an exquisite methodology capable of defining the timing of enhanced permeability of macromolecules in tumors after irradiation. Such information might be applied to optimize the efficacy of subsequent or concurrent therapies including radiolabeled antibodies or other anticancer agents in combination with external beam therapies.

Simultaneous imaging of tumor oxygenation and microvascular permeability using Overhauser enhanced MRI

“…Noninvasive methods to obtain information pertaining to tumor microvessel density, vascular permeability, and oxygenation will aid in appropriate treatment choices (8)(9)(10). Monitoring the leakage of exogenously administered tracers from blood vessels can help in assessing tumor vascular permeability (4,8) by dynamic contrastenhanced MRI (DCE-MRI).…”

“…Monitoring the leakage of exogenously administered tracers from blood vessels can help in assessing tumor vascular permeability (4,8) by dynamic contrastenhanced MRI (DCE-MRI). These contrast agents diffuse from the blood circulation into the extravascular extracellular space (EES) at a rate determined by blood perfusion, vascular permeability, and surface area (11).…”

“…However, the endothelial transfer of large contrast agents is distinctly sensitive to the microvascular permeability difference (13,16). DCE-MRI techniques with large molecular mass tracers have been increasingly used in the assessment of tumor vascular permeability (8,13,15). However, despite the positive impact on patient survival, quantitative and noninvasive information regarding the relationship between tumor microvascular permeability and oxygen status is not available.…”

Translational theranostic methodology for diagnostic imaging and the concomitant treatment of malignant solid tumors

“…In addition to Gadomer-17, other spherical monodisperse nanoparticles of the dendrimer sub-class have been extensively studied in more recent decades, for their applications as blood pool agents for blood and lymphatic perfusion MRI [41][42][43], as well as for studying microvascular permeability of hyperpermeable pathology [43][44][45], which include the most biocompatible of the imageable dendrimer sub-class, those employing cyclic tetracarboxylic acid DOTA as the chelate for Gadolinium, and demonstrate biocompatible biophysical character including exterior functionalization, shape and size, happening to fall within the molecular size range of 2 nm to 14 nm: This being the case, however, not much emphasis has been placed on the following two crucial aspects the first being on the applicability of the imageable dendrimer sub-class for therapeutic purposes including those in the optimal size range for selective transvascular drug delivery of chemotherapy into hyperpermeable pathologies such as solid tumors, and the second being, on the applicability of dynamic contrast-enhanced imaging such as dynamic contrastenhanced MRI to non-invasively quantify therapeutic delivery into hyperpermeable pathologies voxel-by-voxel, until most recently [1,3,8,25,26,28,29].…”

Tumor blood vessel visualization

“…Even the use of unconjugated macromolecular contrast agents with paramagnetic properties in dynamic contrast-enhanced MRI (DCE-MRI) enables to assess important features of tumor vascularization. Blood perfusion and vessel permeability for instance (Kobayashi et al, 2004) can be evaluated by measuring the diffusion of contrast agents from blood circulation out of the endothelium into the extravascular space (Ceelen et al, 2006). Combining the routinely used contrast agent Gd-diethylenetriaminepenta-acetic acid (Gd-DTPA) with an oxygen-sensitive paramagnetic agent in a hyperpolarized 1 H-MRI permits the simultaneous visualization of microvascular permeability with tumor oxygen levels (Matsumoto et al, 2009).…”