Conventional versus drug-eluting embolic transarterial chemoembolization with doxorubicin: comparative drug delivery, pharmacokinetics, and treatment response in a rabbit VX2 tumor model.

Abstract

The purpose of this study was to compare intra-tumoral drug delivery, pharmacokinetics, and treatment response after doxorubicin (DOX) conventional (c-) versus drug-eluting embolic (DEE-) transarterial chemoembolization (TACE) in a rabbit VX2 liver tumor model. Twenty-four rabbits with solitary liver tumors underwent c-TACE (n = 12) (1:2 water-in-oil emulsion, 0.6 mL volume, 2 mg DOX) or DEE-TACE (n = 12) (130,000 70-150 µm 2 mg DOX-loaded microspheres). Systemic, intra-tumoral, and liver DOX levels were measured using mass spectrometry up to 7-day post-procedure. Intra-tumoral DOX distribution was quantified using fluorescence imaging. Percent tumor necrosis was quantified by a pathologist blinded to treatment group. Lobar TACE was successfully performed in all cases. Peak concentration (CMAX, µg/mL) for plasma, tumor tissue, and liver were 0.666, 4.232, and 0.270 for c-TACE versus 0.103, 8.988, and 0.610 for DEE-TACE. Area under the concentration versus time curve (AUC, µg/mL ∗ min) for plasma, tumor tissue, and liver were 18.3, 27,078.8, and 1339.1 for c-TACE versus 16.4, 26,204.8, and 1969.6 for DEE-TACE. A single dose of intra-tumoral DOX maintained cytotoxic levels through 7-day post-procedure for both TACE varieties, with a half-life of 1.8 (c-TACE) and 0.8 (DEE-TACE) days. Tumor-to-normal liver DOX ratio was high (c-TACE, 20.2; DEE-TACE, 13.3). c-TACE achieved significantly higher DOX coverage of tumor vs. DEE-TACE (10.8% vs. 2.3%; P = 0.003). Percent tumor necrosis was similar (39% vs. 37%; P = 0.806). In conclusion, in a rabbit VX2 liver tumor model, both c-TACE and DEE-TACE achieved tumoricidal intra-tumoral DOX levels and high tumor-to-normal liver drug ratios, though c-TACE resulted in significantly greater tumor coverage.

• Authors: Ron C Gaba, Ramzy C Khabbaz, Ruth N Muchiri, Joseph D Morrison, Lobna Elkhadragy, William M Totura, Jonathan P Samuelson, Herbert E Whiteley, Ryan L Deaton, Peter L Nguyen, Maria Sverdlov, Jeremy J Johnson, Richard B van Breemen, R Peter Lokken
• Journal: Drug delivery and translational research (Drug Deliv Transl Res) Vol. 12 Issue 5 Pg. 1105-1117 (05 2022) ISSN: 2190-3948 [Electronic] United States
• PMID: 33861419 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021. Controlled Release Society.

Chemical References

• Doxorubicin

Topics

• Animals
• Carcinoma, Hepatocellular
• Chemoembolization, Therapeutic (methods)
• Doxorubicin
• Liver Neoplasms (drug therapy)
• Necrosis (therapy)
• Rabbits
• Treatment Outcome