Oxidative Damage Induced by Phototoxic Pheophorbide a 17-Diethylene Glycol Ester Encapsulated in PLGA Nanoparticles

Antioxidants

Sergey Obydennyi¹  Murad D. Mollaev²  Dmitry Belykh³  Veronika Beganovskaya⁴  Nikita Yabbarov⁵  Elena Nikolskaya⁵  Mariia R. Mollaeva⁵  Margarita Chirkina⁵  Maria Sokol⁵  Olga Startseva⁶ 

[1] Center for Theoretical Problems of Physicochemical Pharmacology, 119334 Moscow, Russia;Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, 117198 Moscow, Russia;Institute of Chemistry of Komi Scientific Centre of the Ural Branch of Russian Academy of Sciences, 167982 Syktyvkar, Russia;JSC Russian Research Center for Molecular Diagnostics and Therapy, 117149 Moscow, Russia;N.M. Emanuel Institute of Biochemical Physics of Russian Academy of Sciences, 119991 Moscow, Russia;Pitirim Sorokin Syktyvkar State University, 167001 Syktyvkar, Russia;

关键词: photodynamic therapy;    photosensitizer;    cellular uptake;    oxidative stress;    reactive oxygen species;    cell death;   

DOI  :  10.3390/antiox10121985

来源: DOAJ

【 摘 要 】

Pheophorbide a 17-diethylene glycol ester (XL-8), is a promising high-active derivative of known photosensitizer chlorin e6 used in photodynamic therapy. However, high lipophilicity and poor tumor accumulation limit XL-8 therapeutic application. We developed a novel XL-8 loaded with poly(D,L-lactide-co-glycolide) nanoparticles using the single emulsion-solvent evaporation method. The nanoparticles possessed high XL-8 loading content (4.6%) and encapsulation efficiency (87.7%) and a small size (182 ± 19 nm), and negative surface charge (−22.2 ± 3.8 mV) contributed to a specific intracellular accumulation. Sustained biphasic XL-8 release from nanoparticles enhanced the photosensitizer photostability upon irradiation that could potentially reduce the quantity of the drug applied. Additionally, the encapsulation of XL-8 in the polymer matrix preserved phototoxic activity of the payload. The nanoparticles displayed enhanced cellular internalization. Flow cytometry and confocal laser-scanning microscopy studies revealed rapid XL-8 loaded nanoparticles distribution throughout the cell and initiation of DNA damage, glutathione depletion, and lipid peroxidation via reactive oxygen species formation. The novel nanoformulated XL-8 simultaneously revealed a significant phototoxicity accompanied with enhanced photostability, in contrast with traditional photosensitizers, and demonstrated a great potential for further in vivo studies.

【 授权许可】

Unknown