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Theranostics 2021; 11(1):79-92. doi:10.7150/thno.45348 This issue Cite

Research Paper

Development and evaluation of an ultrasound-triggered microbubble combined transarterial chemoembolization (TACE) formulation on rabbit VX2 liver cancer model

Doyeon Kim^1*, Jae Hwan Lee^2*, Hyungwon Moon³, Minkyu Seo¹, Hyounkoo Han¹, Hongkeun Yoo¹, Howon Seo^4,5, Jingu Lee^4,5, Sujung Hong^4,5, Pilhan Kim^4,5,6, Hak Jong Lee^2,3,7, Jin Wook Chung^7,8✉, Hyuncheol Kim^1,9✉

1. Department of Chemical & Biomolecular Engineering, Sogang University, 35 Baekbeom-ro, Mapo-gu, Seoul 04107, Republic of Korea.
2. Department of Radiology, Seoul National University Bundang Hospital, 82, Gumi-ro 173beon-gil, Bundang-gu, Seongnam-si, Gyeonggi-do, Republic of Korea.
3. IMGT Co., Ltd., 172 Dolma-ro, Bundang-gu, Seongnam 13605, Republic of Korea.
4. Graduate School of Nanoscience and Technology, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of Korea.
5. KI for Health Science and Technology (KIHST), Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 34141, Republic of Korea.
6. Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 34141, Republic of Korea.
7. Department of Radiology, Seoul National University College of Medicine, Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea.
8. Institute of Radiation Medicine, Seoul National University Hospital, 101, Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea.
9. Department of Biomedical Engineering, Sogang University, 35 Baekbeom-ro, Mapo-gu, Seoul 04107, Republic of Korea.
*Both authors contributed equally to this work.

✉ Corresponding authors: Hyuncheol Kim, Ph.D., Tel: +82-2-705-8922; Fax: +82-2-3273-0331; E-mail: hyuncheolac.kr; and Jin Wook Chung, Tel: 82-2-2072-2057, Fax: 82-2-743-6385; E-mail: chungjwac.kr.

Abstract

Transarterial chemoembolization (TACE) is an image-guided locoregional therapy used for the treatment of patients with primary or secondary liver cancer. However, conventional TACE formulations are rapidly dissociated due to the instability of the emulsion, resulting in insufficient local drug concentrations in the target tumor.

Methods: To overcome these limitations, a doxorubicin-loaded albumin nanoparticle-conjugated microbubble complex in an iodized oil emulsion (DOX-NPs-MB complex in Lipiodol) has been developed as a new ultrasound-triggered TACE formulation.

Results: (1) Microbubbles enhanced therapeutic efficacy by effectively delivering doxorubicin- loaded nanoparticles into liver tumors via sonoporation under ultrasound irradiation (US+). (2) Microbubbles constituting the complex retained their function as an ultrasound contrast agent in Lipiodol. In a rabbit VX2 liver cancer model, the in vivo study of DOX-NPs-MB complex in Lipiodol (US+) decreased the viability of tumor more than the conventional TACE formulation, and in particular, effectively killed cancer cells in the tumor periphery.

Conclusion: Incorporation of doxorubicin-loaded microbubble in the TACE formulation facilitated drug delivery to the tumor with real-time monitoring and enhanced the therapeutic efficacy of TACE. Thus, the enhanced TACE formulation may represent a new treatment strategy against liver cancer.

Keywords: transarterial chemoembolization, ultrasound microbubble, sonoporation, theranostics, nanomedicine, hepatocellular carcinoma

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