Abstract
In many studies for chemoembolization of hepatocellular carcinoma, the Lipiodol emulsion preparation protocols, especially the mixing steps, were unclear or even unrevealed at all. However, doxorubicin (DOX) release may depend on the composition and volume ratio (Lipiodol to DOX solution) of a Lipiodol emulsion. Therefore, we conducted a preclinical study to compare in-vitro drug release and in-vivo pharmacokinetics of DOX from diverse Lipiodol emulsions and drug-eluting beads (DEBs) and to compare the tumor response in a rabbit VX2 carcinoma model. DOX release profiles of four types of Lipiodol emulsions with different media (normal saline or Pamiray as an iodinated contrast medium), volume ratio (Lipiodol to DOX solution), and DEBs were investigated in-vitro. For the in-vivo study, 15 rabbits bearing VX2 carcinoma in the liver were treated with 4∶1 volume ratio Lipiodol emulsion (group A), 1∶1 volume ratio Lipiodol emulsion (group B), and DEBs (group C) chemoembolization. Blood and tissue sampling was conducted to evaluate DOX concentration in plasma and tissues, histological changes, and liver toxicity. The most stable emulsion was formed with Pamiray (including DOX) at a 4∶1 volume ratio. The AUC value of group A was significantly lower than that of group B (p = 0.003) but comparable to that of group C (p = 0.071). The Cmax value of group A was significantly different compared with those of group B (p = 0.004) and C (p = 0.015). The tissue drug concentration in group A was comparable to that in group C (p = 0.251). No viable tumor was detected in rabbits of group A and B. In group C, viable tumor less than 10% was seen in two of the five rabbits. There were no significant differences in liver enzyme levels after the procedure. In conclusion, DOX release and pharmacokinetics of presented emulsion systems depend substantially on their composition. Therefore, Lipiodol emulsion type should be considered when interpreting data and designing new studies dealing with chemoembolization.
Highlights
Transarterial chemoembolization (TACE) has been used globally as a palliative treatment option in patients with unresectable hepatocellular carcinoma (HCC) [1, 2]
Lipiodol-based emulsions exhibit rapid drug release compared with drug-eluting beads (DEBs)
Sustained drug release profiles were observed for the 4:1 volume ratio rather than the 1:1 volume ratio
Summary
Transarterial chemoembolization (TACE) has been used globally as a palliative treatment option in patients with unresectable hepatocellular carcinoma (HCC) [1, 2]. Drug-eluting beads (DEBs) have become popular as drug carriers in Western countries in the past decade [5]. In-vitro studies have claimed that drug elution from DEBs is controlled and sustained, unlike the rapid drug release from Lipiodol emulsions [6, 7]. A recent clinical trial comparing the use of doxorubicin (DOX)-loaded beads versus conventional transarterial chemoembolization (cTACE) demonstrated reduced side effects when using the former despite the DEB’s uncertain survival gain [8]. The Lipiodol emulsion regimen in an in-vitro drug release test was quite inconsistent with its common clinical usage [6]. A comparative study of drug release from DEBs and various kinds of Lipiodol emulsions is warranted
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