Abstract
The aim of this study is to fabricate nanophotosensitizers composed of methoxy poly(ethylene glycol) (mPEG), chlorin e6 (Ce6), and phenylboronic acid pinacol ester (PBAP) with diselenide linkages for reactive oxygen species (ROS)-sensitive photodynamic therapy (PDT) of cervical cancer cells. To fabricate nanophotosensitizers, Ce6 was conjugated with mPEG via selenocystamine linkage and then remaining carboxylic acid groups of Ce6 was attached to PBAP (mPEGseseCe6PBAP conjugates). Nanophotosensitizers of mPEGseseCe6PBAP conjugates were prepared by dialysis method. In transmission electron microscope (TEM) observation, nanophotosensitizers of mPEGseseCe6PBAP conjugates have spherical shapes and their diameters were less than 150 nm. The average diameter of mPEGseseCe6PBAP nanophotosensitizers was 92.7 ± 9.6 nm in particle size analysis. When H2O2 was added to the nanophotosensitizer solution, nanophotosensitizers were sensitively disintegrated according to the H2O2 concentration and then changed from monomodal distribution to multimodal distribution in particle size distribution. Furthermore, Ce6 release from nanophotosensitizers also increased according to the H2O2 concentration. When H2O2 was added to cell culture of HeLa human cervical cancer cells, intracellular Ce6 uptake of nanophotosensitizers were gradually increased according to the H2O2 concentration, indicating that nanophotosensitizers showed ROS-sensitive delivery of Ce6 against cancer cells.As well as free Ce6, nanophotosensitizers in the absence of light irradiation have low intrinsic cytotoxicity against RAW264.7 cells and HeLa cells. However, nanophotosensitizers induced cell death dose-dependently under light irradiation. Especially, nanophotosensitizers showed significantly higher ROS generation and phototoxicity against HeLa cells in vitro. When nanophotosensitizers were intravenously administered to animal tumor xenograft model of HeLa cells, tumor tissues revealed stronger fluorescence intensity than other tissues by light irradiation while absence of light irradiation induced relatively lower fluorescence intensity in tumor tissues, indicating that nanophotosensitizers have sensitivity against oxidative stress in tumor tissues. We suggest that nanophotosensitizers of mPEGseseCe6PBAP conjugates are promising vehicle for PDT of cervical cancer cells.
Highlights
photodynamic therapy (PDT) using photosensitizers is believed to be a safe option for treatment of malignant disorders [1,2,3]
chlorin e6 (Ce6) was attached to amine end group of mPEGsese conjugates
This result supported by in vivo animal tumor imaging study. These results indicated that nanophotosensitizers of mPEGseseCe6PBAP conjugates were reactive oxygen species (ROS)-sensitive nano-carriers for photosensizers and their delivery capacity can be improved by oxidative stress in tumor tissues
Summary
PDT using photosensitizers is believed to be a safe option for treatment of malignant disorders [1,2,3]. PDT has advantages for treatment of squamous or epithelial phenotype of tumors since the penetration depth of light is limited below 15 mm and the photosensitizer efficiently produces ROS within the limits of light irradiation depth [5,6,7]. The PDT approach is promising treatment option for squamous cervical cancer phenotype since the most phenotype of cervical cancer is known to squamous cell carcinoma [12]. In spite of these advantages, the current approach of PDT using traditional photosensitizers still has drawbacks for application in clinical stage
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