Tumor cell-activated “Sustainable ROS Generator” with homogeneous intratumoral distribution property for improved anti-tumor therapy

Abstract

Photodynamic therapy (PDT) holds a number of advantages for tumor therapy. However, its therapeutic efficiency is limited by non-sustainable reactive oxygen species (ROS) generation and heterogeneous distribution of photosensitizer (PS) in tumor. Herein, a “ S ustainable R OS G enerator” (SRG) is developed for efficient antitumor therapy. Methods: SRG was prepared by encapsulating small-sized Mn 3 O 4 -Ce6 nanoparticles (MC) into dendritic mesoporous silica nanoparticles (DMSNs) and then enveloped with hyaluronic acid (HA). Due to the high concentration of HAase in tumor tissue, the small-sized MC could be released from DMSNs and homogeneously distributed in whole tumor. Then, the released MC would be uptaken by tumor cells and degraded by high levels of intracellular glutathione (GSH), disrupting intracellular redox homeostasis. More importantly, the released Ce6 could efficiently generate singlet oxygen ( 1 O 2 ) under laser irradiation until the tissue oxygen was exhausted, and the manganese ion (Mn 2+ ) generated by degraded MC would then convert the low toxic by-product (H 2 O 2 ) of PDT to the most harmful ROS (·OH) for sustainable and recyclable ROS generation. Results: MC could be homogeneously distributed in whole tumor and significantly reduced the level of intracellular GSH. At 2 h after PDT, obvious intracellular ROS production was still observed. Moreover, during oxygen recovery in tumor tissue, ·OH could be continuously produced, and the nanosystem could induce 82% of cell death comparing with 30% of cell death induced by free Ce6. For in vivo PDT, SRG achieved a complete inhibition on tumor growth. Conclusion: Based on these findings, we conclude that the designed SRG could induce sustainable ROS generation, homogeneous intratumoral distribution and intracellular redox homeostasis disruption, presenting an efficient strategy for enhanced ROS-mediated anti-tumor therapy.

Loss of Renewal of Extracellular Vesicles: Harmful Effects on Embryo Development in vitro

“…ROS are a by-product of oxygen metabolism and some are essential in cell signal transduction and homeostasis. 32 ROS production and ROS elimination are balanced in embryos developing in vivo; however, IVC embryos showed an excess of ROS. 33 Excessively high ROS causes damage to lipids, proteins and DNA, abnormal transcription of genes, modulation of autophagy, cellular growth, differentiation, proliferation, apoptosis, and impaired embryonic development.…”

Clustered Cobalt Nanodots Initiate Ferroptosis by Upregulating Heme Oxygenase 1 for Radiotherapy Sensitization

“…After a coincubation at 37 °C for 30 min, a UV–vis–NIR spectrophotometer (Genesys 10S, Thermo Fisher Scientific) was applied to record the absorbance of MB ranging from 400 to 800 nm. Intracellular •OH was traced with a green fluorescent probe (BBoxiProbe ® O26, 1:1000) as recently described [ 59 ] after iCoDMSN treatment for 1 h. For •OH scavenging, the cells were pretreated with 40 µM nicaraven for 2 h. [ 47 ] An EVOS TM M500 Imaging System (Thermo Fisher Scientific) was then employed to capture the fluorescence images. To detect the intracellular ROS levels, 4T1 cells exposed to 100 µg mL −1 iCoDMSNs for 6 h were processed with ionized radiation (γ‐ray, 6 Gy, 1.0 Gy min −1 ).…”

Reactive oxygen species-upregulating nanomedicines towards enhanced cancer therapy

“…Over the past few decades, multiple approaches have been developed to kill tumor cells by generating lethal ROS in situ and causing oxidative damage. 202,203 Importantly, the elevation of intracellular ROS and oxidative stress are capable of sensitizing or synergizing cancer therapies such as CT, PDT, and CDT. 204,205…”