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Hybrid Nanomedicine Fabricated from Photosensitizer-Terminated Metal-Organic Framework Nanoparticles for Photodynamic Therapy and Hypoxia-Activated Cascade Chemotherapy
摘要： During photodynamic therapy (PDT), severe hypoxia often occurs as an undesirable limitation of PDT owing to the O2-consuming photodynamic process, compromising the effectiveness of PDT. To overcome this problem, several strategies aiming to improve tumor oxygenation are developed. Unlike these traditional approaches, an opposite method combining hypoxia-activated prodrug and PDT may provide a promising strategy for cancer synergistic therapy. In light of this, azido-/photosensitizer-terminated UiO-66 nanoscale metal–organic frameworks (UiO-66-H/N3 NMOFs) which serve as nanocarriers for the bioreductive prodrug banoxantrone (AQ4N) are engineered. Owing to the effective shielding of the nanoparticles, the stability of AQ4N is well preserved, highlighting the vital function of the nano-carriers. By virtue of strain-promoted azide–alkyne cycloaddition, the nanocarriers are further decorated with a dense PEG layer to enhance their dispersion in the physiological environment and improve their therapeutic performance. Both in vitro and in vivo studies reveal that the O2-depleting PDT process indeed aggravates intracellular/tumor hypoxia that activates the cytotoxicity of AQ4N through a cascade process, consequently achieving PDT-induced and hypoxia-activated synergistic therapy. Benefiting from the localized therapeutic effect of PDT and hypoxia-activated cytotoxicity of AQ4N, this hybrid nanomedicine exhibits enhanced therapeutic efficacy with negligible systemic toxicity, making it a promising candidate for cancer therapy.
关键词： hypoxia-activated prodrugs,cascade therapy,nanoscale metal–organic frameworks,banoxantrone,photodynamic therapy
更新于2025-09-04 15:30:14
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FK506 suppresses hypoxia-induced inflammation and protects tight junction function via the CaN-NFATc1 signaling pathway in retinal microvascular epithelial cells
摘要： The present study aimed to identify whether FK506 suppresses hypoxia?induced inflammation and protects tight junction function via the calcineurin-nuclear factor of activated T?cells 1 (CaN?NFATc1) signaling pathway in mouse retinal microvascular endothelial cells (mRMECs). The mRMECs were treated with FK506 at different concentrations following the induction of hypoxia. Trans?epithelial electrical resistance (TEER) and cell permeability were examined to measure the integrity of the tight junctions. The concentrations of inflammatory cytokines were measured using reverse transcription-quantitative polymerase chain reaction analysis and enzyme?linked immunosorbent assays. The protein expression levels of zonula occludens-1 (ZO-1) and nuclear factor of activated T?cell 1 (NFATc1) were identified using immunofluorescent microscopy and western blot analysis. The TEER value was decreased following hypoxia, but increased following treatment with FK506 (1 and 10 μM) for 24 and 48 h. The protein expression of ZO?1 was also increased following FK506 treatment for 24 h at 1 and 10 μM. By contrast, following treatment with FK506 (1 and 10 μM) for 24 and 48 h, the elevated cell permeability in the hypoxia group was significantly downregulated. Similarly, the concentrations of inflammatory cytokines, including cyclooxygenase?2, inducible nitric oxide synthase, monocyte chemoattractant protein-1, interleukin?6, intercellular adhesion molecule?1 and vascular cell adhesion molecule?1, were downregulated following treatment with FK506 for 24 h at 1 and 10 μM. Following treatment with FK506, the level of total NFATc1 was downregulated and the level of phosphorylated NFATc1 was upregulated. Taken together, FK506 suppressed injury to the tight junctions and downregulated the expression of inflammatory cytokines in hypoxia?induced mRMECs via the CaN?NFATc1 signaling pathway. This suggests a potentially effective therapy for hypoxia?induced retinal microangiopathy.
关键词： inflammation,hypoxia,tight junction,calcineurin?nuclear factor of activated T?cells 1 signaling pathway,FK506
更新于2025-09-04 15:30:14
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Radiation-responsive scintillating nanotheranostics for reduced hypoxic radioresistance under ROS/NO-mediated tumor microenvironment regulation
摘要： Abstract: Hypoxia-induced radioresistance is the primary reason for failure of tumor radiotherapy (RT). Changes within the irradiated tumor microenvironment (TME) including oxygen, reactive oxygen species (ROS) and nitric oxide (NO) are closely related to radioresistance. Therefore, there is an urgent need to develop new approaches for overcoming hypoxic radioresistance by incorporating TME regulation into current radiotherapeutic strategies. Methods: Herein, we explored a radiation-responsive nanotheranostic system to enhance RT effects on hypoxic tumors by multi-way therapeutic effects. This system was developed by loading S-nitrosothiol groups (SNO, a NO donor) and indocyanine green (ICG, a photosensitizer) onto mesoporous silica shells of Eu3+-doped NaGdF4 scintillating nanocrystals (NSC). Results: Under X-ray radiation, this system can increase the local dosage by high-Z elements, promote ROS generation by X-ray-induced photodynamic therapy, and produce high levels of NO to enhance tumor-killing effects and improve hypoxia via NO-induced vasodilation. In vitro and in vivo studies revealed that this combined strategy can greatly reinforce DNA damage and apoptosis of hypoxic tumor cells, while significantly suppressing tumor growth, improving tumor hypoxia and promoting p53 up-regulation and HIF1α down-regulation. In addition, this system showed pronounced tumor contrast performance in T1-weighted magnetic resonance imaging and computed tomography. Conclusion: This work demonstrates the great potential of scintillating nanotheranostics for multimodal imaging-guided X-ray radiation-triggered tumor combined therapy to overcome radioresistance.
关键词： X-ray induced photodynamic therapy,hypoxia-induced radioresistance,nanoscintillators,multimodal imaging,nitric oxide
更新于2025-09-04 15:30:14