Maltotriose-Chlorin e6 Conjugate Linked via Tetraethyleneglycol as an Advanced Photosensitizer for Photodynamic Therapy. Synthesis and Antitumor Activities against Canine and Mouse Mammary Carcinoma Cells

Atsushi Narumi; Rioko Rachi; Hiromi Yamazaki; Seigou Kawaguchi; Moriya Kikuchi; Hiroyuki Konno; Tomohiro Osaki; Yoshiharu Okamoto; Xiande Shen; Toyoji Kakuchi; Hiromi Kataoka; Akihiro Nomoto; Tomokazu Yoshimura; Shigenobu Yano

doi:10.1021/acsomega.0c06316

Maltotriose-Chlorin e6 Conjugate Linked via Tetraethyleneglycol as an Advanced Photosensitizer for Photodynamic Therapy. Synthesis and Antitumor Activities against Canine and Mouse Mammary Carcinoma Cells

ACS Omega. 2021 Mar 8;6(10):7023-7033. doi: 10.1021/acsomega.0c06316. eCollection 2021 Mar 16.

Authors

Affiliations

¹ Graduate School of Organic Materials Science, Yamagata University, Jonan 4-3-16, Yonezawa 992-8510, Japan.
² Faculty of Engineering, Yamagata University, Jonan 4-3-16, Yonezawa 992-8510, Japan.
³ Graduate School of Science and Engineering, Yamagata University, Yonezawa, Yamagata 992-8510, Japan.
⁴ Joint Department of Veterinary Clinical Medicine, Faculty of Agriculture, Tottori University, Tottori 680-8553, Japan.
⁵ Research Center for Polymer Materials, School of Materials Science and Engineering, Changchun University of Science and Technology, Weixing Road 7989, Jilin 130022, China.
⁶ Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan.
⁷ Department of Applied Chemistry, Graduate School of Engineering, Osaka Prefecture University, 1-1 Gakuen-cho, Naka-ku, Sakai, Osaka 599-8531, Japan.
⁸ KYOUSEI Science Center for Life and Nature, Nara Women's University, Kitauoyahigashi-machi, Nara 630-8506, Japan.

Abstract

Glycoconjugated chlorins represent a promising class of compounds that meet the requirements for the third-generation photosensitizer (PS) for photodynamic therapy (PDT). We have focused on the use of glucose (Glc) to improve the performance of the PS based on the Warburg effect-a phenomenon where tumors consume higher Glc levels than normal cells. However, as a matter of fact, Glc-conjugation has a poor efficacy in hydrophilic modification; thus, the resultant PS is not suitable for intravenous injection. In this study, a Glc-based oligosaccharide, such as maltotriose (Mal₃), is conjugated to chlorin e6 (Ce6). The conjugation is assisted by two additional molecular tools, such as propargyl amine and a tetraethylene glycol (TEG) derivative. This route produced the target Mal₃-Ce6 conjugate linked via the TEG spacer (Mal₃-TEG-Ce6), which shows the required photoabsorption properties in the physiological media. The PDT test using canine mammary carcinoma (SNP) cells suggested that the antitumor activity of Mal₃-TEG-Ce6 is extremely high. Furthermore, in vitro tests against mouse mammary carcinoma (EMT6) cells have been demonstrated, providing insights into the photocytotoxicity, subcellular localization, and analysis of cell death and reactive oxygen species (ROS) generation for the PDT system with Mal₃-TEG-Ce6. Both apoptosis and necrosis of the EMT6 cells occur by ROS that is generated via the photochemical reaction between Mal₃-TEG-Ce6 and molecular oxygen. Consequently, Mal₃-TEG-Ce6 is shown to be a PS showing the currently desired properties.