Quantitative assessment of macromolecular concentration during direct infusion into an agarose hydrogel phantom using contrast-enhanced MRI

Abstract

Convection-enhanced delivery (CED), that is, direct tissue infusion, has emerged as a promising local drug delivery method for treating diseases of the nervous system. Determination of the spatial distribution of therapeutic agents after infusion is important in evaluating the efficacy of treatment, optimizing infusion protocols and improving the understanding of drug pharmacokinetics. In this study, we provide a methodology to determine the concentration distribution of Gd-labeled tracers during infusion using contrast-enhanced magnetic resonance imaging (MRI). To the best of our knowledge, MR studies that quantify concentration profiles for CED have not been previously reported. The methodology utilizes intrinsic material properties (T(1) and R(1)) and reduces the effect of instrumental factors (e.g., inhomogeneity of MR detection field). As a methodology investigation, this study used an agarose hydrogel phantom as a tissue substitute for infusion. An 11.1-T magnet system was used to image infusion of Gd-DTPA-labeled albumin (Gd-albumin) into the hydrogel. By using data from preliminary scans, Gd-albumin distribution was determined from the signal intensity of the MR images. As a validation test, MR-derived concentration profiles were found comparable to both results measured directly using quantitative optical imaging and results from a computational transport model in porous media. In future studies, the developed methodology will be used to quantitatively monitor the distribution of Gd tracer following infusion directly into tissues.

Figure 1

Schematic of the infusion system setup.

Figure 2

Schematic of the optical imaging method used to measure the concentration of Evans blue labeled Gd-Albumin in the hydrogel slice is shown in (A). Part (B) shows recorded grayscale optical images and part (C) shows the calculated concentration maps. The conversion from the pixel intensity to the dye concentration was based on Beer's law [27].

Figure 3

Plot of the theoretical relationship between concentration and signal intensity used to determine optimal infusate concentration (T₁-weighted imaging; Eq. (6)). Parameter values were based on our measurements (see Results).

Figure 4

(A) Evolution of T₁-weighted MR signal during infusion of Gd-Albumin into 1% agarose hydrogel at a rate of 0.29 μL/min (transverse image at approximate center of infusion site; the cannula is perpendicular to the transverse plane; slice thickness = 1 mm). (B) The signal profile in radial direction was obtained by sampling in the small rectangular regions of interest (ROIs) (~20 pixels in each rectangle). The final signal profile was obtained by sampling in the orthogonal directions symmetric around the infusion site. This figure only shows the sampling in the positive horizontal direction. The infusion cannula/site was identified by a black dot in the image center. (C) Contours of MR signal intensity at time = 91 min.

Figure 5

MR-derived concentration of Evans blue labeled Gd-Albumin compared with profiles measured directly using quantitative optical imaging in a 1 mm thick hydrogel slice. R² = 0.94 and 0.92 at time = 30 and 91 min, respectively. Error bars are the standard deviation (n = 12) of the optical measures.

Figure 6

MR-derived concentration of Gd-Albumin compared with predicted porous media transport profiles at time = 30 and 91 min. Concentration was normalized by dividing by the maximum MR-derived concentration, 6.4 mg/mL. D_eff = 7.12 and 5.0 (10^-11 m²/s) were experimentally measured at temperatures 37 and 25°C, respectively, by Liang et al. [29]. D_eff = 6.75 (10^-11 m²/s) was the optimal diffusivity obtained in this study. For D_eff = 7.12, 6.75, and 5.0 (10^-11 m²/s), R² = 0.91, 0.91, and 0.84 for t = 91 min, and 0.91, 0.92, and 0.92 for t = 30 min, respectively.