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

The emergence of X-ray-induced photodynamic therapy (X-PDT) holds tremendous promise for clinical deep-penetrating cancer therapy. However, the clinical application of X-PDT in cancer treatment is still limited due to the hypoxic property of cancerous tissue, the inherent antioxidant system of tumor cells, and the difficulty in matching the absorption spectra of photosensitizers. Herein, a versatile core-shell radiosensitizer (SCNPs@DMSN@CeOx-PEG, denoted as SSCP) was elaborately designed and constructed to enhance X-PDT by coating tunable mesoporous silica on nanoscintillators, followed by embedding the cerium oxide nanoparticles in situ. The obtained SSCP radiosensitizer demonstrated a distinct blue-shift in the ultraviolet light region, so that it could perfectly absorb the ultraviolet light converted by the SCNPs core, resulting in the formation of photoinduced electron-hole (e--h+) pairs separation to generate reactive oxygen species (ROS). In addition, the cerium oxide exhibits high glutathione consumption to heighten ROS accumulation, and catalase-like activity to alleviate the hypoxia, which further enhances the efficiency of radiotherapy. Benefiting from the abundant Lu and Ce elements, the computed tomography imaging performance of SSCP is about 3.79-fold that of the clinical contrast agent (iohexol), which has great potential in both preclinical imaging and clinical translation.

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

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 LiYF4:Ce scintillator and graphitic carbon nitride nanosheets for on-demand generation of highly cytotoxic peroxynitrite (ONOO-). By simply adjusting the Ce3+ 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.

Near Infrared-Triggered Theranostic Nanoplatform with Controlled Release of HSP90 Inhibitor for Synergistic Mild Photothermal and Enhanced Nanocatalytic Therapy with Hypoxia Relief.

Mild photothermal therapy (PTT, <45 °C) can prevent tumor metastasis and heat damage to normal tissue, compared with traditional PTT (>50 °C). However, its therapeutic efficacy is limited owing to the hypoxic tumor environment and tumor thermoresistance owing to the overproduction of heat shock proteins (HSPs). Herein, a near-infrared (NIR)-triggered theranostic nanoplatform (GA-PB@MONs@LA) is designed for synergistic mild PTT and enhanced Fenton nanocatalytic therapy against hypoxic tumors. The nanoplatform is fabricated by the confined formation of Prussian blue (PB) nanoparticles in mesoporous organosilica nanoparticles (MONs), followed by the loading of gambogic acid (GA), an HSP90 inhibitor, and coating with thermo-sensitive lauric acid (LA). Upon NIR irradiation, the photothermal effect (44 °C) of PB not only induces apoptosis of tumor cells but also triggers the on-demand release of GA, inhibiting the production of HSP90. Moreover, the delivered heat simultaneously enhances the catalase-like and Fenton activity of PB@MONs@LA in an acidic tumor microenvironment, relieving the tumor hypoxia and promoting the generation of highly toxic •OH. In addition, the nanoplatform enables magnetic resonance/photoacoustic dual-modal imaging. Thus, this study describes a distinctive paradigm for the development of NIR-triggered theranostic nanoplatforms for enhanced cancer therapy.