On-Demand Generation of Peroxynitrite from an Integrated Two-Dimensional System for Enhanced Tumor Therapy

Abstract

Nanosystem-mediated tumor radiosensitization strategy combining the features of X-ray with infinite penetration depth and high atomic number elements shows considerable application potential in clinical cancer therapy. However, it is difficult to achieve satisfactory anticancer efficacy using clinical radiotherapy for the majority of solid tumors due to the restrictions brought about by the tumor hypoxia, insufficient DNA damage, and rapid DNA repair during and after treatment. Inspired by the complementary advantages of nitric oxide (NO) and X-ray-induced photodynamic therapy, we herein report a two-dimensional nanoplatform by the integration of the NO donor-modified LiYF 4 :Ce scintillator and graphitic carbon nitride nanosheets for on-demand generation of highly cytotoxic peroxynitrite (ONOO − ). By simply adjusting the Ce 3+ doping content, the obtained nanoscintillator can realize high radioluminescence, activating photosensitive materials to simultaneously generate NO and superoxide radical for the formation of ONOO − in the tumor. Obtained ONOO − effectively amplifies therapeutic efficacy of radiotherapy by directly inducing mitochondrial and DNA damage, overcoming hypoxia-associated radiation resistance. The level of glutamine synthetase (GS) is downregulated by ONOO − , and the inhibition of GS delays DNA damage repair, further enhancing radiosensitivity. This work establishes a combinatorial strategy of ONOO − to overcome the major limitations of radiotherapy and provides insightful guidance to clinical radiotherapy.

Alternative Strategy to Optimize Cerium Oxide for Enhanced X-ray-Induced Photodynamic Therapy

“…Scintillating nanoparticles (SCNPs) are usually used to convert high-energy X-rays into ultraviolet–visible (UV–vis) light for activating the PSs, which are then transferred to molecular oxygen in solution to generate reactive oxygen species (ROS). − The infinite overlap between the emission spectrum of SCNPs (energy donors) and the absorption spectrum of PSs (acceptors) is vital for the X-PDT process. Besides, SCNPs usually contain a high nuclear charge (high- Z ) element with radiosensitization properties.…”

Monolayer LDH Nanosheets with Ultrahigh ICG Loading for Phototherapy and Ca2+-Induced Mitochondrial Membrane Potential Damage to Co-Enhance Cancer Immunotherapy

“…Compared to the height of M-LDH (2.07 nm), the height of MICaP also increases to 5.26 nm after being coated by Ca 3 (PO 4 ) 2 in Figure S2. 45 Meanwhile, the high-angle annular dark-field scanning TEM (HAADF-STEM) image (Figure 1b) and elemental mapping TEM images of MICaP (Figure 1c−h) also prove that Ca 3 (PO 4 ) 2 is successfully coated on MI nanosheets. Moreover, the antisymmetric stretch peak of PO 4 3− at 1040 cm −1 of MICaP is further confirmed by FT-IR, verifying the successful coating of Ca 3 (PO 4 ) 2 (Figure 1j).…”

“…After loading ICG and covering with a Ca 3 (PO 4 ) 2 shell, the dimension of MICaP is enlarged to 312.42 ± 20.42 nm in Figure a, and these results are consistent with the equivalent hydrodynamic diameter measured by DLS (Figure i). Compared to the height of M-LDH (2.07 nm), the height of MICaP also increases to 5.26 nm after being coated by Ca 3 (PO 4 ) 2 in Figure S2 . Meanwhile, the high-angle annular dark-field scanning TEM (HAADF-STEM) image (Figure b) and elemental mapping TEM images of MICaP (Figure c–h) also prove that Ca 3 (PO 4 ) 2 is successfully coated on MI nanosheets.…”

Radiation-Triggered Selenium-Engineered Mesoporous Silica Nanocapsules for RNAi Therapy in Radiotherapy-Resistant Glioblastoma

“…Different from high atomic number (high-Z)-based radiosensitizers, 46 metronidazole with a 2-nitroimidazole group showed a significant radiosensitization effect in hypoxic tumors 47 due to their ability to stabilize ROS-induced oxidative DNA damage. We measured radiosensitization by our P(MNs)-Ang2 construct that carries two metronidazole polymers, PLL-P(MNs) and PGA-P(MNs).…”