Abstract
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.
Highlights
We designed a passive delivery system based on XL-8 loaded PLGA NPs to increase
We revealed a partial overlapping of MitoSox Red, DCF, and XL-8 fluorescence, suggesting the PS accumulation in mitochondria, which agreed with previous reports that described bacteriochlorins and phtalocyanins intracellular localization [45,46]
The XL-8 treated samples demonstrated a higher loss of membrane potential (MMP) over XL-8-NPs treated sample, which may correlate with high lipophilicity and mitochondrial specificity of free PS. These results revealed an activation of both apoptosis and ferroptosis pathways after
Summary
Photodynamic therapy (PDT) emerged around 120 years ago but still remains in high demand in modern medicine [1]. The current PDT application is significantly expanding; it is already applied in the treatment of cancer, atherosclerosis, microbial, and fungal diseases, the stimulation of immune response, and the reduction of adipogenesis and lipogenesis, etc. The PDT mechanism is based on the photosensitizer (PS) transition to the excited state under light irradiation and follows the formation of reactive oxygen species (ROS) 4.0/). Antioxidants 2021, 10, 1985 and free radicals that result in apoptosis or necrosis [6]. In an excited triplet state, PS promotes the formation of singlet oxygen (type II mechanism) or superoxide anion, hydrogen peroxide, and hydroxyl radical (type I mechanism) [7].
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