Zhengze Yu

A Near-Infrared Triggered Nanophotosensitizer Inducing Domino Effect on Mitochondrial Reactive Oxygen Species Burst for Cancer Therapy.

Photodynamic therapy (PDT) is a well-established modality for cancer therapy, which locally kills cancer cells when light irradiates a photosensitizer. However, conventional PDT is often limited by the extremely short lifespan and severely limited diffusion distance of reactive oxygen species (ROS) generated by photosensitizer, as well as the penetration depth of visible light activation. Here, we develop a near-infrared (NIR) triggered nanophotosensitizer based on mitochondria targeted titanium dioxide-coated upconversion nanoparticles for PDT against cancer. When irradiated by NIR laser, the nanophotosensitizer could produce ROS in mitochondria, which induced the domino effect on ROS burst. The overproduced ROS accumulated in mitochondria, resulting in mitochondrial collapse and irreversible cell apoptosis. Confocal fluorescence imaging indicated that the mitochondrial targeting and real-time imaging of ROS burst could be achieved in living cells. The complete removal of tumor in vivo confirmed the excellent therapeutic effect of the nanophotosensitizer.

Real-Time Imaging of Mitochondrial Hydrogen Peroxide and pH Fluctuations in Living Cells Using a Fluorescent Nanosensor

Mitochondrial reactive oxygen species (ROS) and pH fluctuations are closely correlated with mitochondrial dysfunctions, which are implicated in various human diseases including neurodegenerative disorders and cancers. Simultaneously monitoring the changes of ROS and pH of mitochondria remains a major challenge in the mitochondrial biology. In this study, we develop a novel mitochondria-targeted fluorescent nanosensor for real-time imaging of the fluctuations of hydrogen peroxide (H2O2) and pH in living cells. The fluorescence probes for detecting pH and H2O2 were loaded in the small-sized mesoporous silica nanoparticles (MSN). Then the polyethylenimine was attached to cap the pores of MSN, the triphenylphosphonium was further modified to target mitochondria in living cells. Confocal fluorescence imaging indicated that the nanosensor could effectively target mitochondria and successfully achieved real-time imaging of mitochondrial H2O2 and pH fluctuations in living cells. Notably, this is a single nanosensing system that is capable of visualizing multiple subcellular analytes at the same time and position by multicolor fluorescence imaging. The current approach can provide a promising tool to investigate the interplaying roles of various subcellular analytes in living cells.

Ratiometric Fluorescence Nanoprobes for Subcellular pH Imaging with a Single-Wavelength Excitation in Living Cells

Abnormal pH values in the organelles are closely associated with inappropriate cellular functions and many diseases. Monitoring subcellular pH values and their variations is significant in biological processes occurring in living cells and tissues. Herein, we develop a series of ratiometric fluorescence nanoprobes for quantification and imaging of pH values with a single-wavelength excitation in cytoplasm, lysosomes, and mitochondria. The nanoprobes consist of mesoporous silica nanoparticles assembled with aminofluorescein as the recognition unit for pH measurement and ethidium bromide as reference fluorophore. Further conjugation of subcellular targeting moiety enables the nanoprobes to specifically target lysosome and mitochondria. Confocal fluorescence imaging demonstrated that the nanoprobes could effectively monitor the pH fluctuations from 5.0 to 8.3 in living cells by ratio imaging with 488 nm excitation. Subcellular pH determination and imaging in lysosome and mitochondria could also be achieved in different conditions. The current method can offer a general strategy to determine subcellular analytes and investigate the interactions in biological samples.

Hollow Mesoporous Silica Nanoparticles with Tunable Structures for Controlled Drug Delivery

A size-controllable and facile synthetic strategy has been developed to fabricate a series of hollow mesoporous silica nanoparticles (HMSNs) with tunable hollow cores or shell thicknesses by employing gold nanoparticles (Au NPs) and cetyltrimethylammonium bromide (CTAB) as dual templates. Various sizes of Au NPs and different amounts of tetraethyl orthosilicate contributed to structure-tailored mesoporous silica-coated Au NPs. After calcination, CTAB molecules were completely removed, and Au NPs could still support the silica shell due to the high melting point. HMSNs were ultimately obtained by etching Au NPs. Applications of HMSNs as nanocarriers for delivering drugs were investigated. Significantly, it was flexible and convenient to control drug-loading/releasing behavior of HMSNs just by tuning the hollow cores or shell thicknesses. Intracellular experiments have proven that HMSNs are suitable for delivering drugs. We anticipate that this study could provide an important avenue for the synthesis of HMSNs and further contribute to advancing practical applications of HMSNs in drug delivery systems.

A DNA Tetrahedron Nanoprobe with Controlled Distance of Dyes for Multiple Detection in Living Cells and in Vivo

Multicomponent quantitative detection in living samples is becoming increasingly important; however, the current detection strategy may cause fluorescence self-quenching and reduce the sensitivity of detection. To solve the problem, we develop a DNA tetrahedral nanoprobe to control the dyes distance for simultaneous detection of multiple analytes. Compared to mesoporous silica nanoparticles based nanoprobes, the DNA tetrahedral nanoprobes display enhanced fluorescence intensities due to partially avoiding the fluorescence resonance energy transfer. Confocal fluorescence images show that the nanoprobes are capable of detecting and visualizing pH and O2•- in living cells under a single wavelength excitation. In an inflammation model for mice, the nanoprobes simultaneously image the down-regulation of pH and up-regulation of O2•-. We expect that the current strategy can provide new opportunities in designing probes for multiplexed detection with reduced self-quenching and enhanced sensitivity.

Dual-Ratiometric Fluorescent Nanoprobe for Visualizing the Dynamic Process of pH and Superoxide Anion Changes in Autophagy and Apoptosis

Autophagy and apoptosis are closely associated with various pathological and physiological processes in cell cycles. Investigating the dynamic changes of intracellular active molecules in autophagy and apoptosis is of great significance for clarifying their inter-relationship and regulating mechanism in many diseases. In this study, we develop a dual-ratiometric fluorescent nanoprobe for quantitatively differentiating the dynamic process of superoxide anion (O2•-) and pH changes in autophagy and apoptosis in HeLa cells. A rhodamine B-loaded mesoporous silica core was used as the reference, and fluorescence probes for pH and O2•- measurement were doped in the outer layer shell of SiO2. Then, chitosan and triphenylphosphonium were modified on the surface of SiO2. The experimental results showed that the nanoprobe is able to simultaneously and precisely visualize the changes of mitochondrial O2•- and pH in HeLa cells. The kinetics data revealed that the changes of pH and O2•- during autophagy and apoptosis in HeLa cells were significantly different. The pH value was decreased at the early stage of apoptosis and autophagy, whereas the O2•- level was enhanced at the early stage of apoptosis and almost unchanged at the initial stage of autophagy. At the late stage of apoptosis and autophagy, the concentration of O2•- was increased, whereas the pH was decreased at the late stage of autophagy and almost unchanged at the late stage of apoptosis. We hope that the present results provide useful information for studying the effects of O2•- and pH in autophagy and apoptosis in various pathological conditions and diseases.

Nuclear-Targeted Photothermal Therapy Prevents Cancer Recurrence with Near-Infrared Triggered Copper Sulfide Nanoparticles

Clinical cancer treatments nowadays still face the challenge of recurrence due to the residual cancer cells and minute lesions in surgeries or chemotherapies. To effectively address the problem, we introduce a strategy for constructing cancer cell nuclear-targeted copper sulfide nanoparticles (NPs) with a significant photothermal effect to completely kill residual cancer cells and prevent local cancer recurrence. The NPs could directly target the tumor cells and further enter the nucleus by the surface modification of RGD and TAT peptides. Under the irradiation of 980 nm near-infrared laser, the NPs rapidly increase the temperature of the nucleus, destroy the genetic substances, and ultimately lead to an exhaustive apoptosis of the cancer cells. In vivo experiments show that the designed NPs could effectively treat cancer and prevent the return of cancer with a single laser irradiation for 5 min. The photothermal therapy strategy with nuclear targeting for cancer therapy and anti-recurrence will provide more possibilities to develop efficient platforms for treating cancer.

A simple approach for glutathione functionalized persistent luminescence nanoparticles as versatile platforms for multiple in vivo applications

We develop a simple method by constructing glutathione (GSH) conjugated persistent luminescence nanoparticles (PLNPs-GSH) as versatile platforms for multiple biological applications. PLNPs-GSH possess enhanced water solubility and contains a large number of active groups, which offer opportunities for further modification with different functional groups.