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Early response evaluation of doxorubicin-nanoparticle-microbubble therapy in orthotopic hepatocellular carcinoma rat model using contrast-enhanced ultrasound and intravoxel incoherent motion-diffusion MRI

Ultrasonography 2022년 41권 1호 p.150 ~ 163
양현경, 김정훈, 이학종, 문형원, 류화성, 한준구,
소속 상세정보
양현경 ( Yang Hyun-Kyung ) - Yonsei University College of Medicine Severance Hospital Department of Radiology
김정훈 ( Kim Jung-Hoon ) - Seoul National University College of Medicine Department of Radiology
이학종 ( Lee Hak-Jong ) - Seoul National University College of Medicine Department of Radiology
문형원 ( Moon Hyung-Won ) - IMGT Co. Ltd.
류화성 ( Ryu Hwa-Seong ) - Pusan National University Yangsan Hospital Department of Radiology
한준구 ( Han Joon-Koo ) - Seoul National University College of Medicine Department of Radiology

Abstract


Purpose: This study aimed to apply doxorubicin-loaded nanoparticle microbubble (Dox-NP-MB) therapy in an orthotopic rat model of hepatocellular carcinoma (HCC) and investigate the utility of contrast-enhanced ultrasound (CEUS) and intravoxel incoherent motion diffusion-weighted magnetic resonance imaging (IVIM-DWI) for response evaluation.

Methods: Twenty-eight N1S1 HCC model rats were treated with either Dox-NP-MB (group [G] 1, n=8), doxorubicin (Dox) alone (G2, n=7), nanoparticle microbubbles alone (G3, n=7), or saline (G4, control, n=6) on days 0 and 7, and were sacrificed on day 11. IVIM-DWI and CEUS were performed before each treatment and before euthanasia. Efficacy was estimated by the percentage of tumor volume growth inhibition compared with control. Toxicity was assessed by body weight changes and blood tests. Post-treatment changes in IVIM-DWI and CEUS parameters were analyzed.

Results: Tumor volume growth was inhibited by 48.4% and 90.2% in G1 and G2 compared to G4, respectively. Compared to G2, G1 had a significantly lower degree of body weight change (median, 91.0% [interquartile range, 88.5%-97.0%] vs. 88.0% [82.5%-88.8%], P<0.05) and leukopenia (1.75×103 cells/μL [1.53-2.77] vs. 1.20×103 cells/μL [0.89-1.51], P<0.05). After the first treatment, an increase in peak enhancement, wash-in rate, and wash-in perfusion index on CEUS was observed in G3 and G4 but suppressed in G1 and G2; the apparent diffusion coefficients, true diffusion coefficients, and perfusion fractions significantly increased in G1 and G2 compared to baseline (P<0.05).

Conclusion: Dox-NP-MB showed reduced Dox toxicity. Early changes in some CEUS and IVIM-DWI parameters correlated with the therapeutic response.

키워드

Hepatocellular carcinoma; Theranostic nanomedicine; Animal models; Ultrasonography; Diffusion magnetic resonance imaging

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