Microgel Bioreactors for Cancer Cell Targeting by pH-Dependent Generation of Radicals
| Autor: | Martin Jakubec, Vojtěch Klimša, František Štěpánek, Vlastimil Král, Monika Majerská, Silvie Rimpelová |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Cell Survival
Radical Pharmaceutical Science 02 engineering and technology medicine.disease_cause 030226 pharmacology & pharmacy HeLa 03 medical and health sciences 0302 clinical medicine Bioreactors Drug Discovery medicine Tumor Microenvironment Humans Particle Size Cytotoxicity chemistry.chemical_classification Tumor microenvironment Reactive oxygen species Microgels Oncogene biology Chemistry Laccase Hydrogen-Ion Concentration 021001 nanoscience & nanotechnology biology.organism_classification Oxidative Stress Cancer cell Biophysics Molecular Medicine 0210 nano-technology Reactive Oxygen Species HT29 Cells Oxidative stress HeLa Cells |
| Zdroj: | Molecular pharmaceutics. 16(7) |
| ISSN: | 1543-8392 |
| Popis: | The lack of specificity of traditional cytostatics and increasing resistance of cancer cells represent important challenges in cancer therapy. One of the characteristics of cancer cells is their intrinsic oxidative stress caused by higher metabolic activity, mitochondrial malfunction, and oncogene stimulation. This feature can be exploited in the pursuit of more selective cancer therapy, as there is increasing evidence that cancer cells are more sensitive to elevated concentrations of reactive oxygen species than normal cells. In this study, we demonstrate a new concept for cancer cell targeting by in situ production of radicals under physiological conditions. The biologically active radicals are produced in the milieu of cancer cells by enzymatic conversion from an inactive precursor, 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid)diammonium salt, by using miniature bioreactors represented by cell-sized microgels containing immobilized laccase. We utilize the pH-dependent activity of laccase to generate radicals only at a lower pH (5.7-6.1) that is characteristic of the tumor microenvironment. The composition of the microgels was optimized so as to allow sufficient substrate and radical diffusion, high enzyme activity, and stability under physiological conditions. The functionality of this system was evaluated on three cancer cell lines (HeLa, HT-29, and DLD1) and the cytotoxicity of in situ-produced radicals was successfully proven in all cases. These results demonstrate that cancer cell targeting by in situ-generated radicals using miniature enzymatic reactors may represent an alternative to traditional cytostatics. In particular, the pH-dependence of radical generation and their short-lived nature can ensure localized functionality in the tumor microenvironment and thereby reduce systemic side-effects. |
| Databáze: | OpenAIRE |
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