Regional convection-enhanced delivery of gadolinium-labeled albumin in the rat hippocampus in vivo

Abstract

Convection-enhanced delivery (CED) has emerged as a promising method of targeted drug-delivery for treating central nervous system (CNS) disorders, but the influence of brain structure on infusate distribution is unclear. We have utilized this approach to study extracellular transport and distribution of a contrast agent in the hippocampus, a complex structure susceptible to CNS disorders. The magnetic resonance (MR) contrast agent diethylene triamene penta-acetic acid chelated gadoliniumlabeled albumin (Gd-albumin), tagged with Evans blue dye, was directly infused into the dorsal and ventral hippocampus of seven male Sprague-Dawley rats. The final distribution profile of the contrast agent, a product of CED and limited diffusion, was observed in vivo using high-resolution T1-weighted MR imaging at 11.1 Tesla. Dense cell layers, such as the granule cell layer of the dentate gyrus and the pyramidal cell layer of CA1, appeared to be barriers to transport of the tracer. Threedimensional distribution shape and volume (V d ) differences, between the dorsal and ventral hippocampus infusions, were determined from the MR images using a semi-automatic segmentation routine (Dorsal V d = 23.4 ± 1.8 μl, Ventral V d = 36.4 ± 5.1 μl). Finer structural detail of the hippocampus was obtained using a combination of histological analysis and fluorescence imaging. This study demonstrates that CED has the potential to target all regions of the hippocampus and that tracer distribution is influenced by infusion site, underlying structure and circuitry, and extent of backflow. Therefore, CED, combined with high-resolution MR imaging, may be a useful strategy for delivering therapeutics for the treatment of CNS disorders affecting the hippocampus.

Jeannette Wilkins Award: Can Locally Delivered Gadolinium Be Visualized on MRI? A Pilot Study

“…Our data for distribution of locally delivered Gd-DTPA in soft tissue are consistent with in vivo tissue delivery measured by Adams et al [1], Nelson et al [22], and Owen et al [24]; with MRI data for drug distribution from a local infusion in vitro by Raghavan et al [26]; and with the local distribution after infusion into brain tissue in vivo [4] (Table 2). Our data showing visualization of Gd-DTPA over time with an MRI are consistent with Astary et al [4] and Raghavan et al [26], who also showed that gadolinium distribution can be seen to change with time.…”

“…Failures in treatment are often attributed to inadequate débridement; however, it is not possible to know if adequate antimicrobial levels are achieved throughout the postdébridement wound in these failures. Clinically used delivery vehicles include acrylic bone cement (PMMA) and CaSO 4 , although many other vehicles, including collagen, have been investigated. Antimicrobial release from these vehicles ranges in vitro from 100% of contained antimicrobial over 24 hours for collagen [17] to 3-5% over 1 month for low-porosity PMMA [25].…”

“…Local delivery of chemotherapy agents and gadolinium to the brain has been imaged with MRI [4,26,28] and then mathematically modeled to improve catheter placement for local delivery [28]. Although antimicrobials cannot be visualized on MRI, Gd-DTPA, a T1 contrast agent, may function as an imaging surrogate for gentamicin.…”

Voxelized Model of Brain Infusion That Accounts for Small Feature Fissures: Comparison With Magnetic Resonance Tracer Studies

“…This assumption is valid when the infusion rate is low and pressure during infusion in tissue is small, or if the initial deformation occurs over a much shorter time scale than CED infusion time. Perivascular transport was not accounted for in this CED model, but has been sometimes observed in infusion into the rat hippocampus [16]. In porous media, the continuity of fluid equation is…”

“…Connected fissures are a set of smaller fluid-filled spaces between tissue borders that can provide another low resistance pathway for interstitial fluid and infusate diversion. During CED, infusate may leak into fissures, and this phenomena has been observed following CED infusion into dorsal and ventral hippocampi [16,17], as well as at other CED infusion sites [2,18]. To the best of our knowledge, previous computational brain transport and CED models have not accounted for the impact of these fissures on drug delivery.…”