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Preclinical Therapeutic Evaluation of Lenvatinib-Eluting Microspheres for Transcatheter Arterial Chemoembolization of Hepatocellular Carcinoma

  • Laboratory Investigation
  • Interventional Oncology
  • Published:
CardioVascular and Interventional Radiology Aims and scope Submit manuscript

Abstract

Purpose

To evaluate the preclinical in vivo therapeutic response of Lenvatinib-eluting microspheres (LEN-EM) transcatheter arterial chemoembolization (LEN-TACE) in an hepatocellular carcinoma (HCC) rat model.

Methods

Magnetic resonance imaging (MRI) visible LEN-EM was fabricated with poly(lactide-co-glycolide) and iron oxide nanoparticles by a double-emulsion method. The morphology, LEN loading/release kinetics, and MRI contrast effect of LEN-EM were evaluated. For in vivo study, N1S1 HCC rats were treated with LEN-TACE (LEN: 2.4 mg/kg, n = 5) using LEN-EM, systemic LEN (LEN: 0.4 mg/kg, oral gavage daily for 7 days, n = 5), control (intra-arterial (IA) saline infusion, n = 5), and non-tumor control (n = 3). Tumor size changes were measured for 2 weeks. Histology, comparative LEN plasma concentration, hematologic markers, liver profile, and serum chemistry among the groups were measured.

Results

LEN-EM with 33 µm in average size was prepared in an optimized emulsion process. LEN loading efficiency was 58.7%. LEN was continuously released for 500 h. LEN-TACE showed the delivered LEN-EM surrounding tumor tissue in MRI-T2* images. The LEN-TACE group demonstrated a statistically significant larger tumor volume reduction compared to the other groups at 2 weeks post-procedure. Quantification data of Terminal deoxynucleotidyl transferase dUTP nick end labeling positive cells confirmed increased cancer cell death in the LEN-TACE group compared to control groups. Additional histology, hematologic markers, and liver profiles showed minimal side effects of LEN-TACE.

Conclusion

LEN-TACE using IA delivery of LEN-EM demonstrated an effective therapeutic efficacy in an HCC rat animal model.

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Abbreviations

HCC:

Hepatocellular carcinoma

IA:

Intra-artery

LEN:

Lenvatinib

LEN-Ems:

Lenvatinib-eluting microspheres

TACE:

Transcatheter arterial chemoembolization

HIF-1a:

Hypoxia-inducible factor-1a

VEGF:

Vascular endothelial growth factor

FDA:

Food and Drug Administration

VEGFR:

Vascular endothelial growth factor receptor

FGFR:

Fibroblast growth factor receptor

IONP:

Iron oxide nanoparticles

PLGA:

Poly(lactide-co-glycolide)

PBS:

Phosphate-buffered saline

TUNEL:

Terminal deoxynucleotidyl transferase dUTP nick end labeling

ALT:

Alanine aminotransferase

AST:

Aspartate aminotransferase

SDMA:

Serum symmetric dimethylarginine

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Acknowledgements

This work was mainly supported by grants R01CA218659 and R01EB026207 from the National Cancer Institute and National Institute of Biomedical Imaging and Bioengineering. Also, this work was supported by the Center for Translational Imaging and Mouse Histology and Phenotyping Laboratory at Northwestern University. Illustrations were originally created by authors through Biorender.

Funding

This study was funded by grants R01CA218659 and R01EB026207 from the National Cancer Institute and National Institute of Biomedical Imaging and Bioengineering.

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Authors and Affiliations

  1. Department of Radiology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA

    Jason Pe, Bongseo Choi, Hyunjun Choi, Soon Woo Kwon & Dong-Hyun Kim

  2. Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL, USA

    Dong-Hyun Kim

  3. Department of Biomedical Engineering, University of Illinois at Chicago, Chicago, IL, USA

    Hyunjun Choi & Dong-Hyun Kim

  4. Department of Biomedical Engineering, McCormick School of Engineering, Northwestern University, Evanston, IL, USA

    Dong-Hyun Kim

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Pe, J., Choi, B., Choi, H. et al. Preclinical Therapeutic Evaluation of Lenvatinib-Eluting Microspheres for Transcatheter Arterial Chemoembolization of Hepatocellular Carcinoma. Cardiovasc Intervent Radiol 45, 1834–1841 (2022). https://doi.org/10.1007/s00270-022-03242-8

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