Spatiotemporal Quantification of Local Drug Delivery Using MRI

Abstract

Controlled release formulations for local, in vivo drug delivery are of growing interest to device manufacturers, research scientists, and clinicians; however, most research characterizing controlled release formulations occurs in vitro because the spatial and temporal distribution of drug delivery is difficult to measure in vivo. In this work, in vivo magnetic resonance imaging (MRI) of local drug delivery was performed to visualize and quantify the time resolved distribution of MRI contrast agents. Three-dimensional T 1 maps (generated from T 1-weighted images with varied T R) were processed using noise-reducing filtering. A segmented region of contrast, from a thresholded image, was converted to concentration maps using the equation 1/T 1 = 1/T 1,0 + R 1 C, where T 1,0 and T 1 are the precontrast and postcontrast T 1 map values, respectively. In this technique, a uniform estimated value for T 1,0 was used. Error estimations were performed for each step. The practical usefulness of this method was assessed using comparisons between devices located in different locations both with and without contrast. The method using a uniform T 1,0, requiring no registration of pre- and postcontrast image volumes, was compared to a method using either affine or deformation registrations.

Antimicrobial Distribution From Local Delivery Depends on Dose

“…As in previous investigations, Gd-DTPA transport away from the depot was seen to penetrate into transected muscle (Fig. 2) [14] and along tissue planes but not across intact fascia or bone (Fig. 3).…”

“…The Gd-DTPA distribution from local delivery observed in this study was maintained above the imaging threshold for less than a month. The MRI threshold used in our study and previously reported work is approximately 14 lg/mL Gd-DTPA [14]. Gd-DTPA has 2.8 times as many active molecules as gentamicin sulfate, based on molecular weight and the amount of sulfate in gentamicin sulfate.…”

“…We studied the distribution of Gd-DTPA as an antimicrobial surrogate from Gd-DTPA-loaded bone cement (GLBC) as previously described [13,14]. Standardized GLBC implants made with three Gd-DTPA loads were implanted in a rabbit wound model and imaged at 7, 14, and 33 days.…”

“…A series of T1-weighted RARE images (TR: 1463, 2000, 3000, and 5000 milliseconds) were obtained. Previously published image processing techniques were used to produce concentration maps and three-dimensional projections of the volume of distribution of the locally delivered Gd-DTPA [14]. All voxels with Gd-DTPA concentration values of 14 lg/mL or more were used to construct concentration maps and volume projections.…”

“…However, tissue biopsies inherently do not provide continuous spatial and temporal distributions. Our laboratory has previously reported on gadolinium-labeled diethylenetriamine pentaacetic acid (Gd-DTPA) as an antimicrobial surrogate and the ability of 7-T MRI to quantify the distribution of Gd-DTPA over a period of 5 hours after local delivery throughout surgical wounds [13,14]. Although Gd-DTPA is not intracellularly transported [14] and does not bind protein as some antimicrobials do at systemic concentrations, it does have similar molecular weight, solubility, and diffusivity and will be locally transported very similarly to many water-soluble antimicrobials [14].…”