Zhang, Xing-Jie, Han, Gui-Yan, Guo, Chang-Yong, Ma, Zhi-Qiang, Lin, Mei-Yu, Wang, Yuan, Miao, Zhen-Yuan, Zhang, Wan-Nian, Sheng, Chun-Quan, and Yao, Jian-Zhong
This study aimed to improve the biological effectiveness and pharmacokinetic properties of chlorin e 6 , a second-generation photosensitizer (PS), for tumor photodynamic therapy (PDT). Herein, the novel 31-hexyloxy chlorin e 6 -based 152- or 131-amino acid derivatives 3a , 3b , 3c and 8 were synthesized and their photophysical properties and in vitro bioactivities such as phototoxicity against A549, HeLa and melanoma B16–F10 cells, reactive oxygen species (ROS) production and subcellular localization were evaluated. In addition, preferred target compounds were also investigated for their in vivo pharmacokinetic in SD rats and in vivo antitumor efficacies in C57BL/6 mice bearing melanoma B16–F10 cells. Apparently, simultaneous introduction of amino acid residue and n -hexyloxy chain in chlorin e 6 made a significant improvement in photophysical properties, ROS production, in vitro and in vivo PDT efficacy. Encouragingly, all target compounds showed higher in vitro phototoxicity than Talaporfin, and that 3c (152-Lys) exhibited strongest phototoxicity and highest dark toxicity/phototoxicity ratio, followed by 8 (131-Asp), 3a (152-Asp) and 3b (152-Glu). Moreover, in vivo PDT antitumor efficacy of 3a , 3c and 8 was all better than that of Talaporfin, and that both 3c and 8 had stronger PDT antitumor efficiency than 3a. The overall results suggested that these novel 31-hexyloxy chlorin e 6 -based 152- or 131-amino acid derivatives, especially 3c and 8 , might be potential antitumor candidate drugs for clinical treatment of melanoma by PDT. Image 1 • The 31-hexyloxy chlorin e 6 -based 152- or 131-amino acid derivatives were synthesized. • In vitro photodynamic activity and mechanism of target compounds were investigated. • In vivo antitumor potency and pharmacokinetic of target compounds were evaluated. • In vitro and in vivo PDT antitumor efficacy of 3a , 3c , 8 were better than Talaporfin. • In vitro and in vivo PDT antitumor efficacy of 3c and 8 were superior to 3a. [ABSTRACT FROM AUTHOR]