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Kilcup N¹, Tonkopi E², Abraham RJ³, Boyd D⁴, Kehoe S⁵.

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Abstract

The purpose of this study was to synthesize and optimize intrinsically radiopaque composite embolic microspheres for sustained release of doxorubicin in drug-eluting bead transarterial chemoembolization. Using a design of experiments approach, 12 radiopaque composites composed of polylactic-co-glycolic acid and a radiopaque glass (ORP5) were screened over a range of compositions and examined for radiopacity (computed tomography) and density. In vitro cell viability was determined using an extract assay derived from each composition against the human hepatocellular carcinoma cell line, HepG2. Mathematical models based on a D-Optimal response surface methodology were used to determine the preferred radiopaque composite. The resulting radiopaque composite was validated and subsequently loaded with doxorubicin between 0 and 1.4% (wt% of polylactic-co-glycolic acid) to yield radiopaque composite drug-eluting beads. Thereafter, the radiopaque composite drug-eluting beads were subjected to an elution study (up to 168 h) to determine doxorubicin release profiles (UV-Vis spectroscopy) and in vitro cell viability. Radiopaque composites evaluated for screening purposes had densities between 1.28 and 1.67 g.cm(-3), radiopacity ranged between 211 and 1450HU and cell viabilities between 91 and 106% were observed. The optimized radiopaque composite comprised 23 wt% polylactic-co-glycolic acid and 60 wt% ORP5 with a corresponding density of 1.63 ± 0.001 g.cm(-3), radiopacity at 1930 ± 44HU and cell viability of 89 ± 7.6%. Radiopaque composite drug-eluting beads provided sustained doxorubicin release over 168 h. In conclusion, the mathematical models allowed for the identification and synthesis of a unique radiopaque composite. The optimized radiopaque composite had similar density and cell viability to commercially available embolic microspheres. It was possible to preload doxorubicin into radiopaque composite drug-eluting beads, such that sustained release was possible under simulated physiological conditions.

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