A Targeted Nanosystem for Detection of Inflammatory Diseases via Fluorescent/Optoacoustic Imaging and Therapy via Modulating Nrf2/NF-κB Pathways.

Inflammatory diseases are sometimes devastating and notoriously difficult to treat. Precisely modulating inflammatory signaling pathways is a promising approach for treating inflammatory diseases. Herein, a multifunctional nanosystem is developed for active targeting, activatable imaging and on-demand therapy against inflammatory diseases through modulating inflammatory pathways. A chromophore-drug dyad (QBS-FIS) is synthesized by linking a chromophore and a Nrf2 (nuclear factor E2-related factor) activator fisetin through boronate bond which serves as fluorescence quencher and ROS (reactive oxygen species)-responsive linker. QBS-FIS molecules form nanoparticles in water and are coated with macrophage cell membrane to ensure active targeting toward inflammation site. To further improve therapeutic efficacy, a NF-kB (nuclear-factor kappa-light-chain-enhancer of activated B cells) inhibitor thalidomide is co-encapsulated to afford the nanosystem (QBS-FIS&Thd@MM). Upon administration into mice, the nanosystem migrates to inflammatory site and pathological ROS therein cleaves the boronate bonds, thereby activating the chromophore for imaging liver/kidney inflammatory diseases for disease diagnosis and recovery evaluation via fluorescence and optoacoustic imaging as well as releasing the active drugs for treating acute liver inflammation through activating Nrf2 pathway and inhibiting NF-kB pathway. The 3D multispectral optoacoustic tomography imaging is applied to precisely locate the inflammatory foci in a spatiotemporal manner.

CRISPR/Cas9-edited triple-fusion reporter gene imaging of dynamics and function of transplanted human urinary-induced pluripotent stem cell-derived cardiomyocytes.

PURPOSE: To investigate the post-transplantation behaviour and therapeutic efficacy of human urinary-induced pluripotent stem cell-derived cardiomyocytes (hUiCMs) in infarcted heart. METHODS: We used clustered regularly interspaced short palindromic repeats/CRISPR-associated nuclease 9 (CRISPR/Cas9) technology to integrate a triple-fusion (TF) reporter gene into the AAVS1 locus in human urine-derived hiPSCs (hUiPSCs) to generate TF-hUiPSCs that stably expressed monomeric red fluorescent protein for fluorescence imaging, firefly luciferase for bioluminescence imaging (BLI) and herpes simplex virus thymidine kinase for positron emission tomography (PET) imaging. RESULTS: Transplanted cardiomyocytes derived from TF-hUiPSCs (TF-hUiCMs) engrafted and proliferated in the infarcted heart as monitored by both BLI and PET imaging and significantly improved cardiac function. Under ischaemic conditions, TF-hUiCMs enhanced cardiomyocyte (CM) glucose metabolism and promoted angiogenic activity. CONCLUSION: This study established a CRISPR/Cas9-mediated multimodality reporter gene imaging system that can determine the dynamics and function of TF-hUiCMs in myocardial infarction, which is helpful for investigating the application of stem cell therapy.

Brain metabolic characteristics distinguishing typical and atypical benign epilepsy with centro-temporal spikes.

OBJECTIVES: Atypical benign epilepsy with centro-temporal spikes (BECTS) have less favorable outcomes than typical BECTS, and thus should be accurately identified for adequate treatment. We aimed to investigate the glucose metabolic differences between typical and atypical BECTS using 18F-fluorodeoxyglucose positron emission tomography ([18F]FDG PET) imaging, and explore whether these differences can help distinguish. METHODS: Forty-six patients with typical BECTS, 31 patients with atypical BECTS and 23 controls who underwent [18F]FDG PET examination were retrospectively involved. Absolute asymmetry index (|AI|) was applied to evaluate the severity of metabolic abnormality. Glucose metabolic differences were investigated among typical BECTS, atypical BECTS, and controls by using statistical parametric mapping (SPM). Logistic regression analyses were performed based on clinical, PET, and hybrid features. RESULTS: The |AI| was found significantly higher in atypical BECTS than in typical BECTS (p = 0.040). Atypical BECTS showed more hypo-metabolism regions than typical BECTS, mainly located in the fronto-temporo-parietal cortex. The PET model had significantly higher area under the curve (AUC) than the clinical model (0.91 vs. 0.70, p = 0.006). The hybrid model had the highest sensitivity (0.90), specificity (0.85), and accuracy (0.87) of all three models. CONCLUSIONS: Atypical BECTS showed more widespread and severe hypo-metabolism than typical BECTS, depending on which the two groups can be well distinguished. The combination of metabolic characteristics and clinical variables has the potential to be used clinically to distinguish between typical and atypical BECTS. KEY POINTS: • Distinguishing between typical and atypical BECTS is very important for the formulation of treatment regimens in clinical practice. • Atypical BECTS showed more widespread and severe hypo-metabolism than typical BECTS, mainly located in the fronto-temporo-parietal cortex. • The logistic regression model based on PET outperformed that based on clinical characteristics in classification of typical and atypical BECTS, and the hybrid model achieved the best classification performance.

Unusual Electron Donor-Acceptor Sequenced NIR AIEgen for Highly Efficient Mitochondria-Targeted Cancer Cell Photodynamic Therapy.

Photodynamic therapy (PDT) is recognized to be a promising strategy for anticancer treatment. Considering the progressive application of PDT in clinical trials, highly efficient and photostable photosensitizers (PSs) are in strong demand. Aggregation-induced emission (AIE) based PSs are promising phototheranostic materials for tumor imaging and PDT due to their high fluorescence efficiency and photostability. Herein, a mitochondria-targeted PS, TPA-2TCP with AIE characteristics is developed by adopting an acceptor-π-donor-π-acceptor (A-π-D-π-A) structure. The untypical sequence of the electron donors and electron acceptors endows the derived AIE PS with evident redshift of the absorption and emission, and efficient generation of reactive oxygen species. With the positively charged pyridinium groups, nanoparticulated AIE PS (TPA-2TCP NPs) exhibits high cell binding efficiency towards 4T1 breast cancer cells, leading to the massive cell death via the apoptotic pathway under white light irradiation, demonstrating its potential application in cancer imaging and PDT.

Aggregation-induced Emission Based Fluorogens for Mitochondria-targeted Tumor Imaging and Theranostics.

Occurrence and development of cancer are multifactorial and multistep processes which involve complicated cellular signaling pathways. Mitochondria, as the energy producer in cells, play key roles in tumor cell growth and division. Since mitochondria of tumor cells have a more negative membrane potential than those of normal cells, several fluorescent imaging probes have been developed for mitochondria-targeted imaging and photodynamic therapy. Conventional fluorescent dyes suffer from aggregation-caused quenching effect, while novel aggregation-induced emission (AIE) probes are ideal candidates for biomedical applications due to their large stokes shift, strong photo-bleaching resistance, and high quantum yield. This review aims to introduce the recent advances in the design and application of mitochondria-targeted AIE probes. The comprehensive review focuses on the structure-property relationship of these imaging probes, expecting to inspire the development of more practical and versatile AIE fluorogens (AIEgens) as tumor imaging and therapy agents for preclinical and clinical use.