Abstract

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 3 1 -hexyloxy chlorin e 6 -based 15 2 - or 13 1 -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 (15 2 -Lys) exhibited strongest phototoxicity and highest dark toxicity/phototoxicity ratio, followed by 8 (13 1 -Asp), 3a (15 2 -Asp) and 3b (15 2 -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 3 1 -hexyloxy chlorin e 6 -based 15 2 - or 13 1 -amino acid derivatives, especially 3c and 8 , might be potential antitumor candidate drugs for clinical treatment of melanoma by PDT.