Abstract
Poly(hydroxyethyl acrylate-co-phenyl vinyl sulfide) (P(HEA-co-PVS)), as an oxidizable amphiphilic polymer, was prepared for the fabrication of an oxidation- and temperature-responsive micelle for the delivery of doxorubicin (DOX). The interfacial activity of H2O2-treated P(HEA-co-PVS) was significantly lower than that of the untreated variety, possibly because of the oxidization of PVS. P(HEA-co-PVS) exhibited a lower critical solution temperature (LCST) behavior and the LCST increased upon H2O2 treatment. The copolymer micelles, prepared by the dialysis method, were found to be round particles (less than 100 nm) on TEM micrograph. The release degree of Nile red loaded in the micelles was higher when the H2O2 concentration was higher, possibly because the micelles could be solubilized more readily at a higher H2O2 concentration. The release degree was more strongly dependent on the oxidizing agent concentration when the temperature was higher. DOX loaded in the micelles suppressed the in vitro growth of KB cells (a human cancer cell type originating from the cervix) much more effectively than DOX loaded in an unoxidizable control micelle and free DOX, possibly because the copolymer would undergo an increase in its LCST, lose its amphiphilic property, and the micelles would be disassembled. The DOX-loaded micelles were readily internalized into KB cells, as evidenced by flow cytometry (FACS) and confocal laser scanning microscopy (CLSM).
Highlights
Redox-responsive carriers have been of great interest in the field of drug delivery because they are able to release their payload at the site of action where reducing agents and/or oxidizing one are relatively abundant
If the micelles are exposed to an oxidative environment, the Phenyl vinyl sulfide (PVS) unit can be oxidized to more hydrophilic phenyl vinyl sulfoxide and/or sulfone; the copolymer would undergo an increase in its lower critical solution temperature (LCST), lose its amphiphilic property, and the micelle would be disassembled, resulting in oxidation- and temperature-triggered release (Figure 1)
2-Hydroxyethyl acrylate (HEA, purity: 96%), N,N-dimethylformamide (DMF), phosphotungstic acid hydrate, dimethyl sulfoxide-d6 (DMSO-d6), thiazolyl blue tetrazolium bromide (MTT), fluoroshieldTM with 4’,6-diamidino-2-phenylindole (DAPI), triethylamine, and doxorubicin hydrochloride were purchased from Sigma Aldrich Chemical Co
Summary
Redox-responsive carriers have been of great interest in the field of drug delivery because they are able to release their payload at the site of action where reducing agents and/or oxidizing one are relatively abundant. Oxidation-sensitive drug carriers were prepared to release pharmaceutical agents at the site or in the condition of high reactive oxygen species (ROS) concentration. Since ROS can be created in high concentration in diseases such as rheumatoid arthritis, neurodegenerative diseases, atherosclerosis, diabetes, and cancers, oxidation-sensitive drug carriers can be utilized to release pharmaceutical agents at the diseased sites or in the pathological condition [17,18]. When placed in an oxidative environment, the hydrophobic poly(propylene sulfide) block was converted to more hydrophilic poly(sulfones) and the triblock copolymer lost its amphiphilic property, leading to the disintegration of the vesicle. If the micelles are exposed to an oxidative environment, the PVS unit can be oxidized to more hydrophilic phenyl vinyl sulfoxide and/or sulfone; the copolymer would undergo an increase in its LCST, lose its amphiphilic property, and the micelle would be disassembled, resulting in oxidation- and temperature-triggered release (Figure 1). The oxidation- and temperature-responsive micelles would be able to release their payload in response to the oxidative intracellular condition (inherent intracellular ROS plus DOX-induced oxygen free radicals), leading to enhanced anticancer efficacy
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