RESUMEN
Immunotherapy can enhance primary tumor efficacy, restrict distant growth, and combat lung metastasis. Unfortunately, it remains challenging to effectively activate the immune response. Here, tertiary butyl, methoxy, and triphenylamine (TPA) were utilized as electron donors to develop multifunctional photosensitizers (PSs). CNTPA-TPA, featuring TPA as the donor (D) and cyano as the acceptor (A), excelled in reactive oxygen species (ROS) generation due to its smaller singlet-triplet energy gap (ΔES-T) and larger spin-orbit coupling constant (SOC). Additionally, cyano groups reacted with glutamate (Glu) and glutathione (GSH), reducing intracellular GSH levels. This not only enhanced PDT efficacy but also triggered redox dyshomeostasis-mediated ferroptosis. The positive effects of photodynamic therapy (PDT) and ferroptosis promoted immunogenic cell death (ICD) and immune activation. By further combining anti-programmed cell death protein ligand-1 (anti-PD-L1) antibody, the powerful treatments of ferroptosis-assisted photodynamic immunotherapy significantly eradicated the primary tumors, inhibited the growth of distant tumors, and suppressed lung metastasis. In this study, a three-pronged approach was realized by single-component CNTPA-TPA, which simultaneously served as metal-free ferroptosis inducers, type-I photosensitizers, and immunologic adjuvants for near-infrared fluorescence imaging (NIR FLI)-guided multimodal phototheranostics of tumor. STATEMENT OF SIGNIFICANCE: (1) CNTPA-TPA shared the smallest singlet-triplet energy gap and the largest spin-orbit coupling constant, which boosted intersystem crossing for efficient type-I photodynamic therapy (PDT); (2) Special reactions between cyano groups with glutamate and glutathione in mild conditions restricted the biosynthesis of intracellular GSH. GSH-depletion efficiently induced glutathione peroxidase 4 inactivation and lipid peroxide, resulting in ferroptosis of tumor cells; (3) The combination treatments of ferroptosis-assisted photodynamic immunotherapy induced by single-component CNTPA-TPA with the participation of anti-PD-L1 antibody resulted in increased T-cell infiltration and profound suppression of both primary and distant tumor growth, as well as lung metastasis.
Asunto(s)
Ferroptosis , Inmunoterapia , Fotoquimioterapia , Fármacos Fotosensibilizantes , Ferroptosis/efectos de los fármacos , Fotoquimioterapia/métodos , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/uso terapéutico , Animales , Inmunoterapia/métodos , Humanos , Ratones , Línea Celular Tumoral , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/terapia , Femenino , Especies Reactivas de Oxígeno/metabolismo , Ratones Endogámicos BALB C , Glutatión/metabolismoRESUMEN
PURPOSE: To assess and compare the diagnostic performance of 3D amide proton-transfer-weighted (3D-APTW) imaging, 3D pseudocontinuous arterial spin-labeling (3D-PcASL) imaging, and diffusion-weighted imaging in distinguishing true progression (TP) from treatment response (TR) in posttreatment malignant glioma patients. MATERIALS AND METHODS: Forty-eight patients with suspected tumor recurrence were prospectively enrolled. Histological or longitudinal routine MRI follow-up over six months was assessed to confirm lesion type. The apparent diffusion coefficient (ADC), relative APTWmax (rAPTW), and relative CBFmax values (rCBF) were measured in lesions with enhancing regions on post-gadolinium T1 -weighted MRI. MRI parameters between the TP and TR groups were compared using Student's t tests. In addition, a receiver operating characteristic (ROC) curve was constructed, and the area under the ROC curve (AUC) was calculated to assess the differentiation diagnostic performance of each parameter. RESULTS: The TP group showed a significantly higher rAPTW and rCBF than the TR group; the AUCs of rAPTW and rCBF to distinguish between TP and TR were 0.911 (with sensitivity of 90.3% and specificity of 82.4%) and 0.852 (with sensitivity of 80.6% and specificity of 82.4%), respectively. By adding the rAPTW values to rCBF values, the diagnostic ability was improved from 0.852 to 0.951. ADC showed no significant differences between the TP and TR groups, with an AUC lower than 0.70. CONCLUSION: Both 3D-PcASL and 3D-APTW imaging could distinguish TP from TR, and 3D-APTW had a better diagnostic performance. Combining the rAPTW values and rCBF values achieved a better diagnostic performance.
Asunto(s)
Glioma , Protones , Humanos , Marcadores de Spin , Amidas , Glioma/diagnóstico por imagen , Glioma/terapiaRESUMEN
PURPOSE: The goal of this study was to evaluate the diagnostic performance of 3D amide proton transfer-weighted (3D-APTW) imaging and 3D pseudocontinuous arterial spin labelling (3D-pCASL) alone and in combination in grading gliomas (low-grade glioma (LGG) vs. high-grade glioma (HGG)) and correlating isocitrate dehydrogenase (IDH) mutation status. PROCEDURES: Preoperatively, 81 patients with pathologically confirmed gliomas underwent 3.0-T magnetic resonance imaging (MRI) examinations. The APTW, relative APTW (rAPTW), cerebral blood flow (CBF), and relative CBF (rCBF) values were calculated to evaluate the solid components of the tumours. The MRI parameters were compared in the classification of gliomas by independent- and paired-samples t tests. A receiver operating characteristic (ROC) curve was constructed, and the area under the ROC curve (AUC) was calculated to assess the diagnostic performance of each parameter and the combination of the rAPTW and rCBF values. RESULTS: Patients with HGG showed significantly higher APTW, rAPTW, CBF, and rCBF values than those with LGG (all p < 0.001). In the ROC curve analysis, the AUC of rAPTW was the highest at 0.90. By adding the rAPTW signal to the rCBF values, the diagnostic ability of the combined parameters improved from 0.90 to 0.96. The rAPTW value yielded the highest AUC (0.92) in correlating the IDH mutation status, and the diagnostic ability improved to 0.96 by adding it to the rCBF value. CONCLUSION: 3D-APTW imaging combined with 3D-pCASL imaging may be used to aid assessment of grading glioma and IDH mutation status.