Reactive Oxygen Species-Sensitive Nanophotosensitizers of Methoxy Poly(ethylene glycol)-Chlorin e6/Phenyl Boronic Acid Pinacol Ester Conjugates Having Diselenide Linkages for Photodynamic Therapy of Cervical Cancer Cells

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.

Redox-Sensitive Delivery of Doxorubicin from Nanoparticles of Poly(ethylene glycol)-Chitosan Copolymer for Treatment of Drug-Resistant Oral Cancer Cells

“…As shown in Figure 3 b, specific peaks of the ChitoPEG copolymer, ThdCOOH, and DOX were confirmed at 1.0~4.6 ppm. Since PEG has hydrophilic and stealth properties in blood circulation, ChitoPEGthDOX conjugates may form core–shell nanoparticles, i.e., PEG forms the outer-shell of nanoparticles, while the DOX-thioketal linker-chitosan part forms the core of the nanoparticles [ 26 , 28 ]. Since DOX has hydrophobic properties, DOX aggregated in the core of the nanoparticles.…”

“…For example, the abnormal physiological status of the tumor microenvironment provides an opportunity for drug targeting using nanocarriers, i.e., nanoparticles can be designed to be sensitive to an acidic pH and liberate anticancer agents in the acidic tumor microenvironment [ 24 ]. Elevated redox potential of the tumor microenvironment can also be used to address targeting issues using nanoparticles [ 25 , 26 ]. When anticancer agents are conjugated to nanoparticles via ROS or GSH-sensitive linkers, nanoparticles are able to liberate anticancer agents at a higher ROS or GSH level.…”

“…When anticancer agents are conjugated to nanoparticles via ROS or GSH-sensitive linkers, nanoparticles are able to liberate anticancer agents at a higher ROS or GSH level. These properties facilitate the delivery of anticancer agents that are sensitive to these conditions [ 25 , 26 ]. For example, Lim et al reported that pH-sensitive nanoparticles can improve tumor-specific delivery of a radiosensitizer in a mouse brain tumor model and efficiently provide radiation-induced anticancer therapy against the brain tumor [ 23 ].…”

“…Furthermore, Deng et al reported that ROS-inducible and pH-sensitive nanocarriers can improve the delivery of doxorubicin (DOX) under tumor hypoxia, and thus overcome drug resistance [ 25 ]. When ROS-sensitive nanoparticles with phenyl-boronic acid pinacol esters and diselenide linkages sensitively react with hydrogen peroxide, the release of the anticancer drug can be accelerated at a higher ROS level [ 26 ]. They argued that the anticancer activity was higher at higher levels of ROS in vitro.…”