Increase in tumour permeability following TGF-β type I receptor-inhibitor treatment observed by dynamic contrast-enhanced MRI

Abstract

BACKGROUND: To enhance the success rate of nanocarrier-mediated chemotherapy combined with an anti-angiogenic agent, it is crucial to identify parameters for tumour vasculature that can predict a response to the treatment of the anti-angiogenic agent. METHODS: To apply transforming growth factor (TGF)-b type I receptor (TbR-I) inhibitor, A-83-01, to combined therapy, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was carried out in mice bearing colon 26 cells using gadolinium (Gd)-DTPA and for its liposomal formulation to evaluate changes in tumour microvasculature following A-83-01. Tumour vascular parameters from DCE-MRI were compared with histological assessment and apparent diffusion coefficient of water in tumour generated by diffusion-weighted MRI. RESULTS: Contrary to evaluations reported for anti-angiogenic agents, A-83-01 treatment increased the initial area under the Gd concentration -time curve (IAUGC 60 ), volume transfer constant (K trans ) and fractional plasma volume (v p ) significantly within 24 h, that was positively related to a-smooth muscle actin-positive pericyte coverage and tumour cell proliferation, and was correlated inversely with the apparent diffusion coefficient. The vascular function of the tumour improved by A-83-01 treatment was well assessed on post-liposomal Gd-DTPA-enhanced MR images, which predicted delivery of a liposomal drug to the tumour. CONCLUSION: These findings suggest that DCE-MRI and, in particular, K trans and v p quantitation, provide important additional information about tumour vasculature by A-83-01 treatment.

Hyperpolarized 13C Spectroscopy Detects Early Changes in Tumor Vasculature and Metabolism after VEGF Neutralization

“…For hyperpolarized experiments, a 24-mm diameter surface coil tuned to 13 C (100 MHz) was positioned over the tumor. In all experiments, transverse 1 H "pilot" images were acquired for tumor localization using a spin-echo pulse sequence [repetition time (TR), 500 milliseconds; echo time (TE), 10 milliseconds; field-of-view (FOV), 35 C; Cambridge Isotope Laboratories) were hyperpolarized as described previously (26,28,33). Samples were polarized in a GE Healthcare DNP prototype hyperpolarizer for 45 minutes before dissolution in 6 mL of buffer (26).…”

“…Inversion recovery data were fitted, pixel-by-pixel, to a monoexponential function and spin-echo images were converted to relaxation rate maps (26). The Gd 3þ -DTPA concentration curve was evaluated in all tumor-containing slices with a manually delineated region of interest (ROI), and the integrated area under the curve up to 60 (AUC 60 ) or 600 seconds was calculated for each ROI (34,35). Data shown are from the central slice through the tumor, to avoid artifacts from skin perfusion in the outer slice and flow within the torso in the inner slice.…”

Detection of Tumor Response to a Vascular Disrupting Agent by Hyperpolarized 13C Magnetic Resonance Spectroscopy

“…The assembly was placed in a quadrature 1 H-tuned volume coil (Varian), in a 9.4-T vertical wide-bore magnet (Oxford Instruments). Transverse 1 H images were acquired using a gradient-echo pulse sequence [30 pulse; repetition time (TR), 300 milliseconds; echo time (TE), 2.2 milliseconds; field-of-view (FOV), 35 Â 35 mm in a data matrix of 256 Â 256, with 2 averages per increment; slice thickness, 2 mm, and 21 transverse slices]. The tumor slice for hyperpolarized experiments was selected from these images, and a slice-selective excitation pulse and acquire sequence was used for 13 C spectroscopy.…”

“…The effect of Gd-DTPA on transverse relaxation was assumed to be negligible at the short TE used. The area under DR 1 curve (AUC) was calculated from a region of interest covering the whole tumor (30,31). Statistical significance was tested using Prism (Graphpad), with 1-way analysis of variance (ANOVA) on the Gd-DTPA uptake curves and a paired 2-tailed t test at the 95% confidence interval for the AUC.…”

Folate-Targeted Gadolinium-Lipid-Based Nanoparticles as a Bimodal Contrast Agent for Tumor Fluorescent and Magnetic Resonance Imaging

“…The usefulness of small molecular contrast agents in clinical practice is limited by low specificity for the intended target tissues, and need to use high concentrations, for signal enhancement. To overcome these shortcomings, a wide variety of macromolecules and nanoparticulate systems have been developed as Gd-based MRI contrast agents, including proteins, 1) dendrimers, 2) polymers, [3][4][5] liposomes, [6][7][8] and micelles. [9][10][11] Since nano-sized carrier systems passively extravasate from the circulation through the vascular gaps of the tumor neovasculature, a process termed the enhanced permeability and retention (EPR) effect, 12) they have been utilized for the delivery of contrast agents and therapeutic agents to tumors.…”