Oxime-based 19-nortestosterone–pheophorbideaconjugate: bimodal controlled release concept for PDT
| Autor: | Pavel Drašar, Petr Bartůněk, Vladimíra Pavlíčková, Eliška Staňková, Zdeňka Rottnerová, Tomáš Ruml, Michal Jurášek, Kamil Záruba, Marketa Simkova, Jan Fähnrich, Silvie Rimpelová, David Sedlák, Oldřich Lapčík, David Kodr |
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| Rok vydání: | 2019 |
| Předmět: |
Chlorophyll
Surface Properties medicine.medical_treatment Cell Biomedical Engineering Antineoplastic Agents Photodynamic therapy 02 engineering and technology 010402 general chemistry 01 natural sciences Structure-Activity Relationship chemistry.chemical_compound Cell Line Tumor Oximes LNCaP medicine Humans Testosterone General Materials Science Photosensitizer Particle Size Cell Proliferation Photosensitizing Agents Dose-Response Relationship Drug Molecular Structure Chemistry Optical Imaging General Chemistry General Medicine 021001 nanoscience & nanotechnology In vitro 0104 chemical sciences medicine.anatomical_structure Microscopy Fluorescence Photochemotherapy Pheophorbide A Cell culture Cancer research Drug Screening Assays Antitumor 0210 nano-technology Conjugate |
| Zdroj: | Journal of Materials Chemistry B. 7:5465-5477 |
| ISSN: | 2050-7518 2050-750X |
| DOI: | 10.1039/c9tb01301f |
| Popis: | Photodynamic therapy has become a feasible direction for the treatment of both malignant and non-malignant diseases. It has been in the spotlight since FDA regulatory approval was granted to several photosensitizers worldwide. Nevertheless, there are still strong limitations in the targeting specificity that is vital to prevent systemic toxicity. Here, we report the synthesis and biological evaluation of a novel bimodal oxime conjugate composed of a photosensitizing drug, red-emitting pheophorbide a, and nandrolone (NT), a steroid specifically binding the androgen receptor (AR) commonly overexpressed in various tumors. We characterized the physico-chemical properties of the NT-pheophorbide a conjugate (NT-Pba) and singlet oxygen generation. Because light-triggered therapies have the potential to provide important advances in the treatment of hormone-sensitive cancer, the biological potential of this novel specifically-targeted photosensitizer was assessed in prostatic cancer cell lines in vitro using an AR-positive (LNCaP) and an AR-negative/positive cell line (PC-3). U-2 OS cells, both with and without stable AR expression, were used as a second cell line model. Interestingly, we found that the NT-Pba conjugate was not only photodynamically active and AR-specific, but also that its phototoxic effect was more pronounced compared to pristine pheophorbide a. We also examined the intracellular localization of NT-Pba. Live-cell fluorescence microscopy provided clear evidence that the NT-Pba conjugate localized in the endoplasmic reticulum and mitochondria. Moreover, we performed a competitive localization study with the excess of nonfluorescent NT, which was able to displace fluorescent NT-Pba from the cell interior, thereby further confirming the binding specificity. The oxime ether bond degradation was assayed in living cells by both real-time microscopy and a steroid receptor reporter assay using AR U-2 OS cells. Thus, NT-Pba is a promising candidate for both the selective targeting and eradication of AR-positive malignant cells by photodynamic therapy. |
| Databáze: | OpenAIRE |
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