Drug-Eluting Beads Loaded with Antiangiogenic Agents for Chemoembolization: In Vitro Sunitinib Loading and Release and In Vivo Pharmacokinetics in an Animal Model

Abstract

Purpose: The combination of embolic beads with a multi-targeted tyrosine kinase inhibitor that inhibits tumor vessel growth is suggested as an alternative and improvement to the current standard doxorubicin-eluting beads for use in transarterial chemoembolization. This study demonstrates the in vitro loading and release kinetics of sunitinib using commercially available embolization microspheres, and evaluates the in vitro biological efficacy on cell cultures and the resulting in vivo pharmacokinetic profiles in an animal model. Materials and Methods:DC Bead microspheres, 70-150 µm and 100-300 µm (Biocompatibles Ltd., Farnham, United Kingdom), were loaded by immersion in sunitinib solution. Drug release was measured in saline in a USP-approved flow-through apparatus and quantified by spectrophotometry. Activity after release was confirmed in cell culture. For pharmacokinetics and in vivo toxicity evaluation, New-Zealand white rabbits received sunitinib either by intra-arterial injection of 100-300 µm sized beads or per os. Drug concentrations in the plasma and liver tissue were assessed by liquid chromatography-tandem mass spectrometry.Results: Sunitinib loading on beads was close to complete and homogeneous. A total release of 80% in saline was measured, with similar fast release profiles for both sphere sizes. After embolization, drug plasma levels remained below the therapeutic threshold (< 50 ng/ml), but high concentrations at 6 h (14.9 µg/g) and 24 h (3.4 µg/g) were found in the liver tissue.Conclusions: DC Bead microspheres of two sizes were efficiently loaded with sunitinib and displayed a fast and almost complete release in saline. High liver drug concentrations and low systemic levels indicated the potential of sunitinib-eluting beads for use in embolization.

Sunitinib-eluting beads for chemoembolization: Methods for in vitro evaluation of drug release

“…In the Boyd model, B is the exchange rate constant, from which the diffusion coefficient D i of two exchanging ions inside the 140 microsphere (radius r = 156 µm in sunitinib-loaded state (Fuchs et al, 2014)) was calculated.…”

“…To evaluate which set-up represented in vivo conditions best, the obtained release kinetics from 145 the three set-ups were related to in vivo concentrations obtained from previously conducted studies (Fuchs et al, 2014). Briefly, seven healthy New Zealand white rabbits were embolized with 100-300 µm microspheres loaded with 6 mg sunitinib.…”

“…First, plasma sunitinib concentrations in rabbits embolized with sunitinib-eluting spheres (Figure 4 A) (Fuchs et al, 2014) were used. The area under the curve (AUC) of sunitinib in vivo was only related to the in vitro-released cumulative drug amounts in the dialysis insert 320 set-up in a Level A (point-by-point) IVIVC (FDA, 1997) until 24 h (Figure 4 B).…”

“…We have earlier shown DC Bead microspheres (Biocompatibles Ltd.), a widely used commercial type of embolic microspheres, to be an adequate carrier for a new drug, the anti-angiogenic agent sunitinib (Fuchs et al, 2014).…”

“…The protonation of the tertiary amine of the anti-angiogenic drug, sunitinib and consequent incubation with the concentrated spheres 80 results in high capacity of sunitinib loading into the spheres by ionic interaction (Denys et al, 07.06.2012;Fuchs et al, 2014).…”