Kataoka Hiromi, Nishie Hirotada, Hayashi Noriyuki, Tanaka Mamoru, Nomoto Akihiro, Yano Shigenobu, Joh Takashi
Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, Japan.
Department of Applied Chemistry, Graduate School of Engineering, Osaka Prefecture University, 1-1 Gakuen-cho, Naka-ku, Sakai, Osaka, Japan.
Ann Transl Med. 2017 Apr;5(8):183. doi: 10.21037/atm.2017.03.59.
Photodynamic therapy (PDT) is a non-invasive antitumor treatment that uses the combination of a photosensitizer, tissue oxygen, and visible light irradiation to produce cytotoxic reactive oxygen species, predominantly singlet oxygen. Currently, first-generation PDT using porfimer sodium with an excimer dye laser, and second-generation PDT using talaporfin sodium PDT with a semiconductor laser are approved by health insurance for use in Japan. However, the cancer cell specificity and selectivity of these treatments are inadequate. Cancer cells consume higher levels of glucose than normal cells and this phenomenon is known as the Warburg effect. Thus, we developed a third-generation PDT, based on the Warburg effect, by synthesizing a novel photosensitizer, sugar-conjugated chlorin, with increased cancer cell-selective accumulation. Glucose-conjugated chlorin (G-chlorin) PDT showed significantly stronger antitumor effects than second-generation talaporfin PDT. We also found that PDT with G-chlorin induced immunogenic cell death which is characterized by the secretion, release, or surface exposure of damage-associated molecular patterns (DAMPs), including calreticulin (CRT) and the high-mobility group box 1 (HMGB1) protein. Mannose-conjugated chlorin (M-chlorin) PDT which targets the mannose receptors on the surface of cancer cells and tumor-associated macrophages (TAMs) in cancer tissue stroma also showed very strong antitumor effects. These novel PDTs using glucose or M-chlorins stand as new candidates for very effective, next-generation PDTs.
光动力疗法（PDT）是一种非侵入性抗肿瘤治疗方法，它利用光敏剂、组织氧和可见光照射的组合来产生细胞毒性活性氧，主要是单线态氧。目前，使用卟吩姆钠与准分子染料激光的第一代PDT以及使用他拉泊芬钠PDT与半导体激光的第二代PDT在日本已被医疗保险批准使用。然而，这些治疗方法的癌细胞特异性和选择性不足。癌细胞比正常细胞消耗更高水平的葡萄糖，这种现象被称为瓦伯格效应。因此，我们基于瓦伯格效应开发了第三代PDT，通过合成一种新型光敏剂——糖共轭二氢卟吩，其癌细胞选择性积累增加。葡萄糖共轭二氢卟吩（G-二氢卟吩）PDT显示出比第二代他拉泊芬PDT更强的抗肿瘤作用。我们还发现，G-二氢卟吩PDT诱导免疫原性细胞死亡，其特征是包括钙网蛋白（CRT）和高迁移率族蛋白B1（HMGB1）蛋白在内的损伤相关分子模式（DAMPs）的分泌、释放或表面暴露。靶向癌细胞表面甘露糖受体和癌组织基质中肿瘤相关巨噬细胞（TAM）的甘露糖共轭二氢卟吩（M-二氢卟吩）PDT也显示出非常强的抗肿瘤作用。这些使用葡萄糖或M-二氢卟吩的新型PDT成为非常有效的下一代PDT的新候选者。
