Preparation of Radiopaque Drug-Eluting Beads for Transcatheter Chemoembolization

Abstract

Purpose: To develop a simple method to produce radiopaque drug-eluting microspheres (drug-eluting beads [DEBs]) that could be incorporated into the current clinical transcatheter arterial chemoembolization workflow and evaluate their performance in vitro and in vivo.

Materials and methods: An ethiodized oil (Lipiodol; Guerbet, Villepinte, France) and ethanol solution was added to a lyophilized 100-300 µm bead before loading with doxorubicin. These radiopaque drug-eluting beads (DEBs; Biocompatibles UK Ltd, Farnham, United Kingdom) were evaluated in vitro for x-ray attenuation, composition, size, drug loading and elution, and correlation between attenuation and doxorubicin concentration. In vivo conspicuity was evaluated in a VX2 tumor model.

Results: Lipiodol was loaded into lyophilized beads using two glass syringes and a three-way stopcock. Maximum bead attenuation was achieved within 30 minutes. X-ray attenuation of radiopaque beads increased linearly (21-867 HU) with the amount of beads (0.4-12.5 vol%; R(2) = 0.9989). Doxorubicin loading efficiency and total amount eluted were similar to DC Bead (Biocompatibles UK Ltd); however, the elution rate was slower for radiopaque DEBs (P < .05). Doxorubicin concentration linearly correlated with x-ray attenuation of radiopaque DEBs (R(2) = 0. 99). Radiopaque DEBs were seen in tumor feeding arteries after administration by fluoroscopy, computed tomography, and micro-computed tomography, and their location was confirmed by histology.

Conclusions: A simple, rapid method to produce radiopaque DEBs was developed. These radiopaque DEBs provided sufficient conspicuity to be visualized with x-ray imaging techniques.

Conflict of interest statement

Conflicts of interest:

None of the other authors have identified a conflict of interest.

Copyright © 2016 SIR. All rights reserved.

Figures

Figure 1

Overview of Lipiodol loading, washing and attenuation of radiopaque beads. A) Attenuation of 3 vol% agarose bead phantoms made from radiopaque DEBs with variable Lipiodol incubation time periods. B) Attenuation of wash supernatant following Lipiodol loading. C) Representative CT images of radiopaque agarose bead phantoms at different bead concentration (vol%). D) Attenuation of the bead phantoms at different radiopaque bead concentration as shown in C fit with linear regression. Mean ±SEM; n=3–5.

Figure 2

Doxorubicin loading, doxorubicin elution and bead morphology. A) Doxorubicin loading over time (mean±SEM; n=3). B) Doxorubicin elution over time (mean±SEM; n=3). Solid line indicates a fit to first order release kinetics.

Figure 3

MicroCT images and bead composition analysis. Representative microCT images of individual beads showing that radiopaque DEBs have higher attenuation compared to radiopaque beads. The pie charts display composition of wet beads.

Figure 4

Doxorubicin concentration versus attenuation. Radiopaque DEB (75mg doxorubicin/2 ml beads) containing agarose phantoms with various concentrations (0–12.5%) were imaged on a clinical CT scanner. Doxorubicin was extracted from these phantoms and quantified to yield doxorubicin concentration in the original phantom volume. Delta attenuation is used to indicate the change in attenuation since the attenuation of the phantom material was subtracted. These data were fit with linear regression.

Figure 5

Rabbit Vx2 intrahepatic tumor embolized with radiopaque beads in contrast. A pre-embolization digital subtraction angiographic (DSA) image with injection from the proper hepatic artery clearly identified a tumor blush. A post-embolization native image demonstrates radiopaque beads and/or contrast within the hepatic arteries (arrow). A surface shaded display CT image of the embolized liver and a MIP microCT image of the same area (*approximate center of Vx2 tumor location) show radiopaque beads in tumor feeding vessels. Radiopaque beads were suspended in a 1:1 contrast to saline solution prior to delivery. The CT and micro CT are approximately aligned to aid in comparison.

Figure 6

Hematoxylin and eosin images of a rabbit Vx2 tumor surrounded by normal liver embolized with radiopaque beads. A) Radiopaque beads (arrows) are observed in vessels in and around the tumor in this representative section. B) A radiopaque bead located within an artery surrounded by tumor. Note the proximity of this artery to a bile duct, suggesting that a previously existing portal triad was encased by the tumor. C) Radiopaque beads within an artery at the tumor periphery. Note small adjacent satellite metastases within normal liver tissue.

Schematic 1

Summary of procedural steps for generating radiopaque DEBs.