The increasing popularity of porphyrins and hydroporphyrins for application in a variety of biomedical (photodynamic therapy, fluorescence tagging and imaging, photoacoustic imaging) and technical (chemosensing, catalysis, light harvesting) applications is also associated with the growing number of methodologies that enable their solubilization in aqueous media. Natively, the vast majority of synthetic porphyrinic compounds are not water-soluble. Moreover, any water-solubility imposes several restrictions on the synthetic chemist on when to install solubilizing groups in the synthetic sequence, and how to isolate and purify these compounds. This review summarizes the chemical modifications to render synthetic porphyrins water-soluble, with a focus on the work since 2000. Where available, practical data such as solubility, indicators for the degree of aggregation, and special notes for the practicioner are listed. We hope that this review will guide synthetic chemists through the many strategies known to make porphyrins and hydroporphyrins water soluble.

Photodynamic therapy (PDT) with a suitable photosensitizer molecule is a promising anticancer treatment. We evaluated two chlorin molecules as potential photosensitizers, methyl pyropheophorbide a (MPPa) and N-methoxyl purpurinimide (NMPi), against A549 human lung adenocarcinoma cells in vitro as well as in A549 tumor-bearing mice in vivo. Cell viability, microscopy, and FACS analyses were performed for the in vitro studies. MPPa and NMPi showed high phototoxicity in vitro, which was dependent on the concentration of the photosensitizers as well as the light irradiation time. In the animal study, tumor volume change, tumor surface alterations, and H&E and TUNEL staining analyses were performed and compared between small (tumor volume of <50 mm³) and large (tumor volume of >50 mm³) size of initial tumors. MPPa and NMPi showed high anticancer efficacy against small-size tumors, indicating that early treatment with PDT is effective. Especially, repeated two times PDT with NMPi allowed almost complete eradication against small-size tumors. However, MPPa and NMPi were not effective against large-size tumors. In conclusion, the two chlorin derivatives, MPPa and NMPi, show good anticancer efficacy as promising photosensitizers for PDT in vitro and in vivo. Moreover, their activity in vivo was significantly dependent on the initial tumor size in mice, which confirms the importance of early cancer treatment.

The aim of this study is to prepare redox-sensitive nanophotosensitizers for targeted delivery of chlorin e6 (Ce6) against cervical cancer. For this purpose, Ce6 was conjugated with β-cyclodextrin (bCD) via disulfide bond creating nanophotosensitizers that were fabricated for redox-sensitive delivery of Ce6 against cancer cells. bCD was treated with succinic anhydride to synthesize suc-cinylated bCD (bCDsu). After that, cystamine was attached to the carboxylic end of bCDsu (bCDsu-ss) and the amine end group of bCDsu-ss was conjugated with Ce6 (bCDsu-ss-Ce6). Chemical composition of bCDsu-ss-Ce6 was confirmed with 1H and 13C NMR spectra. bCDsu-ss-Ce6 nanophotosensitizers were fabricated by dialysis procedure. They formed small particles with an average particle size of 152.0±23.2 nm and they showed improved singlet oxygen (SO) generation in the aqueous solution under light irradiation and was significantly higher than that of Ce6 alone. Ce6 release rate from bCDsu-ss-Ce6 nanophotosensitizers was accelerated by addition of glutathione (GSH), indicating that bCDsu-ss-Ce6 nanophotosensitizers have re-dox-sensitive photosensitizer delivery capacity. bCDsu-ss-Ce6 nanophotosensitizers have low in-trinsic cytotoxicity against CCD986Sk human skin fibroblast cells as well as Ce6 alone. However, bCDsu-ss-Ce6 nanophotosensitizers showed improved Ce6 uptake ratio, higher reactive oxygen species (ROS) production and phototoxicity compared to those of Ce6 alone. GSH addition resulted in higher Ce6 uptake ratio, ROS generation and phototoxicity than those of Ce6 alone, indicating that bCDsu-ss-Ce6 nanophotosensitizers have redox-sensitive biological activity in vitro against HeLa human cervical cancer cells. At tumor xenograft model using HeLa cells, bCDsu-ss-Ce6 nanophotosensitizers efficiently accumulated in the tumor rather than normal organs, i.e. fluores-cence intensity in tumor tissues was significantly higher than those of other organs while Ce6 alone did not specifically target tumor tissue. These results indicated higher anticancer activity of bCDsu-ss-Ce6 nanophotosensitizers, by efficiently inhibiting growth of tumor in in vivo animal tumor xenograft study.