Kato Akihisa, Kataoka Hiromi, Yano Shigenobu, Hayashi Kazuki, Hayashi Noriyuki, Tanaka Mamoru, Naitoh Itaru, Ban Tesshin, Miyabe Katsuyuki, Kondo Hiromu, Yoshida Michihiro, Fujita Yasuaki, Hori Yasuki, Natsume Makoto, Murakami Takashi, Narumi Atsushi, Nomoto Akihiro, Naiki-Ito Aya, Takahashi Satoru, Joh Takashi
Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
Graduate School of Materials Science, Nara Institute of Science and Technology, Ikoma, Nara, Japan.
Mol Cancer Ther. 2017 Jun;16(6):1124-1132. doi: 10.1158/1535-7163.MCT-16-0670. Epub 2017 Mar 14.
Peritoneal dissemination is a major clinical issue associated with dismal prognosis and poor quality of life for patients with pancreatic cancer; however, no effective treatment strategies have been established. Herein, we evaluated the effects of photodynamic therapy (PDT) with maltotriose-conjugated chlorin (Mal-chlorin) in culture and in a peritoneal disseminated mice model of pancreatic cancer. The Mal-chlorin was prepared as a water-soluble chlorin derivative conjugated with four Mal molecules to improve cancer selectivity. , Mal-chlorin showed superior uptake into pancreatic cancer cells compared with talaporfin, which is clinically used. Moreover, the strong cytotoxic effects of PDT with Mal-chlorin occurred via apoptosis and reactive oxygen species generation, whereas Mal-chlorin alone did not cause any cytotoxicity in pancreatic cancer cells. Notably, using a peritoneal disseminated mice model, we demonstrated that Mal-chlorin accumulated in xenograft tumors and suppressed both tumor growth and ascites formation with PDT. Furthermore, PDT with Mal-chlorin induced robust apoptosis in peritoneal disseminated tumors, as indicated by immunohistochemistry. Taken together, these findings implicate Mal-chlorin as a potential next-generation photosensitizer for PDT and the basis of a new strategy for managing peritoneal dissemination of pancreatic cancer. .
腹膜播散是胰腺癌患者预后不良和生活质量差的一个主要临床问题；然而，尚未确立有效的治疗策略。在此，我们评估了麦芽三糖共轭二氢卟吩（Mal-二氢卟吩）光动力疗法（PDT）在体外培养和胰腺癌腹膜播散小鼠模型中的效果。Mal-二氢卟吩被制备成一种与四个麦芽三糖分子共轭的水溶性二氢卟吩衍生物，以提高对癌症的选择性。与临床使用的替拉泊芬相比，Mal-二氢卟吩在胰腺癌细胞中的摄取表现更优。此外，Mal-二氢卟吩介导的PDT通过凋亡和活性氧生成产生强烈的细胞毒性作用，而单独的Mal-二氢卟吩在胰腺癌细胞中未引起任何细胞毒性。值得注意的是，利用腹膜播散小鼠模型，我们证明Mal-二氢卟吩在异种移植瘤中蓄积，并通过PDT抑制肿瘤生长和腹水形成。此外，免疫组织化学结果表明，Mal-二氢卟吩介导的PDT在腹膜播散肿瘤中诱导了强烈的凋亡。综上所述，这些发现表明Mal-二氢卟吩是一种潜在的下一代PDT光敏剂，也是管理胰腺癌腹膜播散新策略的基础。
