Wavelength-Tuneable Fluorescent Carbon Dots for Nucleic Acid Imaging.

Nucleic acid is one of the most important substances in organisms, and its dynamic changes are closely related to physiological processes. Nucleic acid labeling is conducive to providing important information for the early diagnosis and treatment of pathophysiological processes. Here, we utilized the transfer mechanism between carbon sources and CDs to synthesize wavelength-adjustable N-CDs for the nucleic acid image. Along with the increased graphite nitrogen (from 10.6 to 30.1%) gradually by the precise design of the nitrogen structure in carbon sources (e.g., primary amines, secondary amines, tertiary amines, and liking graphite-nitrogen), the energy gap of CDs reduced, resulting in adjustable wavelength from visible to near-infrared range (from 461 nm/527 nm to 650 nm/676 nm). Furthermore, N-CDs exhibited a selective affinity for nucleic acids, especially RNA. Therefore, N-CDs support an efficient platform for real-time tracking of RNA dynamic changes in cells.

Photoinduced Cuproptosis with Tumor-Specific for Metastasis-Inhibited Cancer Therapy.

Cuproptosis is a novel form of regulated cell death which guarantees to increase the efficacy of existing anticancer treatments that employ traditional apoptotic therapeutics. However, reducing the amount of undesirable Cu ions released in normal tissue and maximizing Cu-induced cuproptosis therapeutic effects at tumor sites are the major challenges. In this study, exploiting the chemical properties of copper ionophores and the tumor microenvironment, a novel method is developed for controlling the valence of copper ions that cause photoinduced cuproptosis in tumor cells. CJS-Cu nanoparticles (NPs) can selectively induce cuproptosis after cascade reactions through H2 O2 -triggered Cu2+ release, photoirradiation-induced superoxide radical (∙O2 - ) generation, and reduction of Cu2+ to Cu+ by ∙O2 - . The generated reactive oxygen species can result in glutathione depletion and iron-sulfur cluster protein damage and further augmented cuproptosis. CJS-Cu NPs effectively suppressed tumor growth and downregulated the expression of metastasis-related proteins, contributing to the complete inhibition of lung metastasis. Ultimately, this study suggests novel avenues for the manipulation of cellular cuproptosis through photochemical reactions.

Activity-Based NIR Enzyme Fluorescent Probes for the Diagnosis of Tumors and Image-Guided Surgery.

Near-infrared (NIR) activatable fluorescent probes have been considered to be the effective edge tools for the investigation of cell biology and disease diagnosis because of their outstanding advantages. Related genes involved in tumor genesis and progression regulate the overexpression of certain enzymes. Owing to the distinctive characteristics of quick reaction time and favorable pharmacokinetics, enzyme-reactive NIR optical probes have shown great potential in the diagnosis of tumorigenesis and in image-guided intraoperative surgeries with high signal-to-noise ratios. In this review, we mainly summarize the latest advancements in enzyme-reactive NIR fluorescent probes from design strategy to biomedical application. Specifically, some challenges and prospects in this field are presented at the end of the review, which will be beneficial to innovatively construct new multifunctional fluorescent probes and actively promote their clinical transformation in the future.

An Activatable AIEgen Probe for High-Fidelity Monitoring of Overexpressed Tumor Enzyme Activity and Its Application to Surgical Tumor Excision.

Monitoring fluctuations in enzyme overexpression facilitates early tumor detection and excision. An AIEgen probe (DQM-ALP) for the imaging of alkaline phosphatase (ALP) activity was synthesized. The probe consists of a quinoline-malononitrile (QM) core decorated with hydrophilic phosphate groups as ALP-recognition units. The rapid liberation of DQM-OH aggregates in the presence of ALP resulted in aggregation-induced fluorescence. The up-regulation of ALP expression in tumor cells was imaged using DQM-ALP. The probe permeated into 3D cervical and liver tumor spheroids for imaging spatially heterogeneous ALP activity with high spatial resolution on a two-photon microscopy platform, providing the fluorescence-guided recognition of sub-millimeter tumorigenesis. DQM-ALP enabled differentiation between tumor and normal tissue ex vivo and in vivo, suggesting that the probe may serve as a powerful tool to assist surgeons during tumor resection.

MicroRNA Detection with Turnover Amplification via Hybridization-Mediated Staudinger Reduction for Pancreatic Cancer Diagnosis.

The occurrence of and development in the early pathological stage of pancreatic cancer has proved to be associated with microRNAs. However, it remains a great challenge to directly monitor low-expression, and downregulation of, microRNA among living cells, tissues, and serum samples. In this work, Staudinger reduction is first applied in intracellular microRNA detection, establishing a set of smart hybridization-mediated Staudinger reduction probes (HMSR-probe) which contain designed oligonucleotide sequences. Meanwhile, 40 serum samples (healthy people (6), patients with pancreatitis (22), and pancreatic cancer patients (12)) are tested for exploring the potential clinical application. Of note, the molecules bound to nucleic acid confine the reactive site to close proximity in a compact space, and nonconnected product from Staudinger reaction facilitates turnover amplification to an ameliorative detection limit (1.3 × 10-15 M). Moreover, compared with qRT-PCR, a low false positive signal and an excellent specificity makes the probe more suitable and convenient for pancreatic cancer diagnosis in blood samples. For practical applications, HMSR-probe enable accurate differentiation in cell and tissue samples under both 488 and 785 nm and have good coherence to known research. As a proof of concept, the reliable results in distinguishing pancreatic cancer patients from different morbid stages might supply a feasible method for endogenous microRNA detection in fundamental research and clinical diagnostics.

A GPX4-targeted photosensitizer to reverse hypoxia-induced inhibition of ferroptosis for non-small cell lung cancer therapy.

Ferroptosis therapy is gradually becoming a new strategy for the treatment of non-small cell lung cancer (NSCLC) because of its active iron metabolism. Because the hypoxic microenvironment in NSCLC inhibits ferroptosis heavily, the therapeutic effect of some ferroptosis inducers is severely limited. To address this issue, this work describes a promising photosensitizer ENBS-ML210 and its application against hypoxia of NSCLC treatment based on type I photodynamic therapy and glutathione peroxidase 4 (GPX4)-targeted ferroptosis. ENBS-ML210 can promote lipid peroxidation and reduce GPX4 expression by generating superoxide anion radicals under 660 nm light irradiation, which reverses the hypoxia-induced resistance of ferroptosis and effectively kills H1299 tumor cells. Finally, the excellent synergistic antitumor effects are confirmed both in vitro and in vivo. We firmly believe that this method will provide a new direction for the clinical treatment of NSCLC in the future.

An Activatable Prodrug Nanosystem for Ultrasound-Driven Multimodal Tumor Therapy and Metastasis Inhibition.

Ultrasound, featuring deep tissue penetration and noninvasiveness, offers a new opportunity to activate functional materials in a tumor-selective manner. However, very few direct ultrasound-responsive redox systems are applicable under therapeutic ultrasound (1 MHz). Herein, the investigations on nanoprodrug of DHE@PEG-SS-DSPE are reported, which exhibit glutathione-activated release of dihydroethidium (DHE) in tumor cells. DHE is stable with good biosafety and is transformed into cytotoxic ethidium to induce DNA damage under medical ultrasound irradiation, accompanied by the generation of reactive oxygen species. Further, DHE@PEG-SS-DSPE could effectively induce ferroptosis through glutathione depletion, lipid peroxide accumulation, and downregulation of glutathione peroxidase 4. In vivo studies confirmed that DHE@PEG-SS-DSPE nanoparticles effectively inhibit both the growth of solid tumors and the expression of metastasis-related proteins in mice, thus effectively inhibiting lung metastasis. This DHE-based prodrug nanosystem could lay a foundation for the design of ultrasound-driven therapeutic agents.

Near-Infrared Light Triggered H2 Generation for Enhanced Photothermal/Photodynamic Therapy against Hypoxic Tumor.

The principle of photochemical transformation has shown significant inspiration on phototherapy of solid tumors. However, both photodynamic therapy (PDT) and photothermal therapy (PTT) can induce stress response of tumor cells, which draw the attention in recent. Herein, an asymmetric and lollipop like nanostructure consisting of gold nanorod/titanium dioxide (l-TiO2 -GNR) is developed by controlling single head growth of titanium dioxide (TiO2 ) on gold nanorods (GNR). Through the reasonable utilization of hot electrons of GNR by 808 nm light irradiation, l-TiO2 -GNR perform type I-PDT, mild PTT (48 °C), and H2 therapy which is efficient for hypoxic tumors. In particular, H2 can downregulate both triphosadenine and heat shock protein which are found to be main source of tumor stress response. l-TiO2 -GNR opens a new window for treatment of hypoxic tumor by the perfect synergy of type I-PDT, mild PTT, and H2 therapy.

Red-Light-Responsive Ru Complex Photosensitizer for Lysosome Localization Photodynamic Therapy.

Photoresponsive ruthenium (Ru) complexes have been extensively studied in the photodynamic therapy (PDT) of cancer. The metal-to-ligand charge transfer (MLCT) absorption maximum of most Ru complexes is located in the short-wavelength visible region, which is well suited for superficial tumors but shows inefficient therapeutic effects for more deep-seated ones. Moreover, Ru complexes are primarily located in the mitochondria or nucleus, always resulting in high levels of dark toxicity and DNA mutation. Herein, we reported a new ruthenium complex (Ru-I) for red-light-triggered PDT. The activation wavelength of Ru-I is successfully extended to 660 nm. Importantly, the complex photosensitizer can be quickly taken up by cancer cells and selectively accumulated in the lysosome, an ideal localization for PDT purposes. Intratumoral injection of Ru-I into tumor-bearing mice achieved excellent therapeutic effects and thus holds great promise for applications in lysosome localization photodynamic therapy.

Ultrasound-degradable serum albumin nanoplatform for in situ controlled drug release.

In this work, bovine serum albumin-based nanoparticles, BSA-ACVA-DOX NPs, were fabricated for ultrasound-driven drug release, and exhibited excellent tissue penetration. Moreover, a pulsatile release of DOX in vivo could be programmed by in vitro (i.e., remotely) switching the ultrasound on and off.

Intracellular MicroRNA imaging using telomerase-catalyzed FRET ratioflares with signal amplification.

Intracellular microRNA (miRNA) detection has attracted increasing attention, resulting in significant achievements. However, the development of an available tool that possesses a satisfactory signal-to-background ratio and high sensitivity for miRNA detection remains challenging. Herein, a class of telomerase-catalyzed FRET (fluorescence resonance energy transfer) ratioflares has been developed for the accurate sensing of low-abundance cancer-related miRNA both in a fluorescence assay and living cell imaging with signal amplification capacity. In this work, endogenous telomerase is led in a miRNA test system with signal amplification for the first time, wherein telomerase extends hexamer telomeric repeats (TTAGGG) using the 3' end of the capture probe as the primer. The synergetic work of telomerase and the catalyst strand (CS) makes the target miRNA circulate in the system, resulting in high sensitivity and an enhanced FRET signal an improved detection limit of 2.27 × 10-15 M. Meanwhile, telomerase-catalyzed FRET ratioflares allow the difference between cancer cells and normal cells to be increased reliably. Furthermore, low false positive signals resulting from chemical interference and minimized system fluctuations are achieved through ratiometric measurements.

Hypoxia-activated NIR photosensitizer anchoring in the mitochondria for photodynamic therapy.

Photodynamic therapy is considered as a promising treatment for cancer, but still faces several challenges. The hypoxic environment in solid tumors, imprecise tumor recognition and the lack of selectivity between normal and cancer cells extremely hinder the applications of photodynamic therapy in clinics. Moreover, the "always on" property of photosensitizers also increases the toxicity to normal tissues when exposed to light irradiation. In this study, a hypoxia-activated NIR photosensitizer ICy-N was synthesized and successfully applied for in vivo cancer treatment. ICy-N is in the inactivated state with low fluorescence whereas its NIR emission (λ em = 716 nm) was induced via reduction caused by nitroreductase at the tumor site. In addition, the reduced product ICy-OH was specially located in the mitochondria and demonstrated a high singlet oxygen production under 660 nm light irradiation, which efficiently induced cell apoptosis (IC50 = 0.63 µM). The in vivo studies carried out in Balb/c mice indicated that ICy-N was suitable for precise tumor hypoxia imaging and can work as an efficient photosensitizer for restraining tumor growth through the PDT process.

Gold nanoparticle-based nano-probe for the colorimetric sensing of Cr3+ and Cr2O72- by the coordination strategy.

In this work, an N-T/gold nanoparticle system was assembled for the convenient and colorimetric identification of Cr based on its coordination chemistry with the thymine derivative (N-T). In addition to the visible colorimetric changes for the qualitative Cr identification, the A630 nm/520 nm values changed linearly with Cr concentration over a range of 0.5-2.5 µM and the detection limits reached 0.03 µM and 0.07 µM for Cr3+ and Cr2O72-, respectively, both of which satisfied the Cr water quality standards of the U.S. EPA, WHO and China. Furthermore, a more convenient method was developed for quantitative determination of Cr concentrations in practical samples based on the Eyedropper function in Microsoft's PowerPoint software, wherein the RGB (red, green and blue) value of the sample could be easily screened in the colorimetric card for a more accurate result with good recovery, avoiding complicated instrumentation.