Comparison of Drug Release and Pharmacokinetics after Transarterial Chemoembolization Using Diverse Lipiodol Emulsions and Drug-Eluting Beads

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.

Lipiodol does not affect the tissue distribution of intravenous doxorubicin infusion in pigs

“…Together with those results, the results of this second part of the study clearly showed that lipiodol alone does not interact directly with DOX membrane transport, and indicate that it is the properties of the complete lipiodol‐based parenteral formulation of DOX that result in its increased tumour‐directed delivery . In fact, it has been demonstrated in other studies that the properties of the formulation may be important for the delivery of DOX to the tumour in vivo . Lipid transport in the body is dependent on lipoproteins, fatty acid binding proteins, lipid transporters (such as ABC transporters), endocytosis and lymphatic drainage .…”

Doxorubicin-loaded poly(lactic-co-glycolic acid) microspheres prepared using the solid-in-oil-in-water method for the transarterial chemoembolization of a liver tumor

“…DOX-PLGA MSs, which corresponded to 50 g of the drug, suspended in DW (0.15 ml) was added to a mini GeBA-flex tube (12-14 kDa molecular weight cut-off; Gene BioApplication Ltd., Kfar Hanagide, Israel). The tube was immersed in the release media (PBS; pH 5.5, 6.8, and 7.4) and incubated in a shaking bath (50 rpm) at 37 • C. Aliquots (200 l) of the release media were collected at determined times (3,6,9,24,48, and 72 h), and an equivalent volume of fresh media was added at each time point. The released amounts of DOX were determined by the high performance liquid chromatography (HPLC) method as previously reported [3].…”

“…The tube was immersed in the release media (PBS; pH 5.5, 6.8, and 7.4) and incubated in a shaking bath (50 rpm) at 37 • C. Aliquots (200 l) of the release media were collected at determined times (3,6,9,24,48, and 72 h), and an equivalent volume of fresh media was added at each time point. The released amounts of DOX were determined by the high performance liquid chromatography (HPLC) method as previously reported [3]. In brief, DOX was quantitatively analyzed by a Waters HPLC system (Waters Co., Milford, MA, USA) equipped with a separation module (Waters e2695), a fluorescence detector (Waters 2475), and a column (reverse-phase, C18, 250 × 4.6 mm, 5 m; Xbridge, Waters Co.).…”

“…Blood samples were collected at 2, 5, 10, 20, 30, and 60 min after the administration, and the plasma was separated by centrifugation. The DOX concentration in the plasma was quantitatively analyzed using the previously reported HPLC method [3]. Briefly, aliquots of the plasma samples (150 l) were mixed with propranolol (10 g/ml), as an internal standard (IS), dissolved in DW (25 l).…”

“…Lipiodol, an iodized oil extracted from poppy seeds, has been used conventionally in TACE for more than three decades [2]. Lipiodol can deliver hydrophilic chemotherapeutic agents as a water-in-oil (W/O) emulsion formulation, but it has an immediate drug release profile and an incomplete embolic effect [2,3].…”