Tumor Growth Suppression With Novel Intra-arterial Chemotherapy Using Epirubicin-entrapped Water-in-oil-in-water Emulsion In Vivo

Hironobu Yanagie; Takashi Fujino; Masashi Yanagawa; Toshimitsu Terao; Takashi Imagawa; Mitsuteru Fujihara; Yasuyuki Morishita; Ryouji Mizumachi; Yuuji Murata; Novriana Dewi; Yuuya Ono; Ichiro Ikushima; Koji Seguchi; Masashi Nagata; Yasumasa Nonaka; Yoshitaka Furuya; Tomoyuki Hisa; Takeshi Nagasaki; Kazuhiko Arimori; Tadao Nakashima; Takumichi Sugihara; Kazuhiro Kakimi; Minoru Ono; Jun Nakajima; Masazumi Eriguchi; Shushi Higashi; Hiroyuki Takahashi

doi:10.21873/invivo.12252

Tumor Growth Suppression With Novel Intra-arterial Chemotherapy Using Epirubicin-entrapped Water-in-oil-in-water Emulsion In Vivo

In Vivo. 2021 Jan-Feb;35(1):239-248. doi: 10.21873/invivo.12252.

Authors

Hironobu Yanagie^{1

2

3}, Takashi Fujino⁴, Masashi Yanagawa⁵, Toshimitsu Terao⁶, Takashi Imagawa⁷, Mitsuteru Fujihara⁸, Yasuyuki Morishita⁹, Ryouji Mizumachi¹⁰, Yuuji Murata¹⁰, Novriana Dewi¹¹, Yuuya Ono⁸, Ichiro Ikushima^{12

13}, Koji Seguchi¹⁴, Masashi Nagata¹⁵, Yasumasa Nonaka¹⁶, Yoshitaka Furuya¹⁷, Tomoyuki Hisa¹⁸, Takeshi Nagasaki¹⁹, Kazuhiko Arimori²⁰, Tadao Nakashima¹³, Takumichi Sugihara¹¹, Kazuhiro Kakimi²¹, Minoru Ono^{2

22}, Jun Nakajima^{2

23}, Masazumi Eriguchi²⁴, Shushi Higashi^{13

14}, Hiroyuki Takahashi^{25

2}

Affiliations

¹ Institute of Engineering Innovation, School of Engineering, The University of Tokyo, Tokyo, Japan; h.yanagie@gmail.com.
² Cooperative Unit of Medicine and Engineering, The University of Tokyo Hospital, Tokyo, Japan.
³ Research Institute of Healthy Living, Niigata University of Pharmacy and Applied Life Sciences, Niigata, Japan.
⁴ Department of Pathology, Saitama Medical University International Medical Center, Hidaka, Japan.
⁵ Veterinary Medical Center, Obihiro University of Agriculture and Veterinary Medicine, Hokkaido, Japan.
⁶ Department of Pharmaceutical Technology, Otsuka Pharmaceutical Factory, Tokushima, Japan.
⁷ Department of Chemical Science and Engineering, Graduate School of Engineering, Kobe University, Hyogo, Japan.
⁸ SPG Techno Ltd. Co., Miyazaki Techno Research Park, Miyazaki, Japan.
⁹ Department of Human and Molecular Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
¹⁰ Department of Pharmacology, Kumamoto Institute Branch, LSI Medience Ltd. Co., Kumamoto, Japan.
¹¹ Laboratory of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences, Niigata, Japan.
¹² Department of Radiology, Miyakonojo Shigun Ishikai Hospital, Miyazaki, Japan.
¹³ Kyushu Medical Resource Foundation, Miyazaki, Japan.
¹⁴ Department of Surgery, Kojin-kai Medical City East Hospital, Miyazaki, Japan.
¹⁵ Department of Pharmacy, Medical Hospital, Tokyo Medical and Dental University, Tokyo, Japan.
¹⁶ Department of Surgery, Keiai-kai Houyou Hospital, Iwate, Japan.
¹⁷ Department of Surgery, Sodegaura Satukidai Hospital, Chiba, Japan.
¹⁸ Tokyo Bunkyo Study Center, The Open University of Japan, Tokyo, Japan.
¹⁹ Department of Bioengineering, Osaka City University Graduate school of Engineering, Osaka, Japan.
²⁰ Department of Pharmacy, Miyazaki Medical University Hospital, Miyazaki, Japan.
²¹ Department of Immunotherapeutics, The University of Tokyo Hospital, Tokyo, Japan.
²² Department of Cardiovascular Surgery, The University of Tokyo Hospital, Tokyo, Japan.
²³ Department of Thoracic Surgery, The University of Tokyo Hospital, Tokyo, Japan.
²⁴ Department of Surgery, Shin-Yamanote Hospital, Japan Anti-Tuberculosis Association, Tokyo, Japan.
²⁵ Institute of Engineering Innovation, School of Engineering, The University of Tokyo, Tokyo, Japan.

Abstract

Background/aim: A mixture of anticancer agents and iodized poppy seed oil (IPSO) has been widely used for intra-arterial chemotherapy of hepatocellular carcinoma. However, the anticancer agents can easily separate from IPSO, so the therapeutic potential is limited. We developed epirubicin-entrapped water-in-oil-in-water emulsion (WOW-Epi) using a double-membrane emulsification technique.

Materials and methods: We delivered WOW-Epi through a hepatic arterial injection to VX2 hepatic tumor rabbit model (1.2 mg/kg).

Results: VX2 tumor growth was selectively suppressed in the WOW-Epi-treated group compared with the control treated groups. The accumulation of WOW in nearby cancer cells was confirmed via electron-microscopy. Endocytosis seemed to be the mechanism underlying the uptake of WOW.

Conclusion: WOW-Epi led to tumour growth suppression in vivo. WOW does not cause toxicity to arterial vessels. WOW-Epi will be hopefully used for repeated intra-arterial chemotherapy to HCC patients in the near future.

Keywords: Water-in-oil-in-water emulsion; epirubicin; hepatocellular carcinoma; intra-arterial chemotherapy.

MeSH terms

Animals
Carcinoma, Hepatocellular* / drug therapy
Emulsions
Epirubicin
Humans
Liver Neoplasms* / drug therapy
Rabbits
Water

Substances

Emulsions
Water
Epirubicin