Jiangwei Tian

Cell-specific and pH-activatable rubyrin-loaded nanoparticles for highly selective near-infrared photodynamic therapy against cancer.

Spatiotemporal control of singlet oxygen ((1)O2) release is a major challenge for photodynamic therapy (PDT) against cancer with high therapeutic efficacy and minimum side effects. Here a selenium-rubyrin (NMe2Se4N2)-loaded nanoparticle functionalized with folate (FA) was designed and synthesized as an acidic pH-activatable targeted photosensitizer. The nanoparticles could specifically recognize cancer cells via the FA-FA receptor binding and were selectively taken up by cancer cells via receptor-mediated endocytosis to enter lysosomes, in which NMe2Se4N2 was activated to produce (1)O2. The pH-controllable release of (1)O2 specially damaged the lysosomes and thus killed cancer cells in a lysosome-associated pathway. The introduction of selenium into the rubyrin core enhanced the (1)O2 generation efficiency due to the heavy atom effect, and the substitution of dimethylaminophenyl moiety at meso-position led to the pH-controllable activation of NMe2Se4N2. Under near-infrared (NIR) irradiation, NMe2Se4N2 possessed high singlet oxygen quantum yield (ΦΔ) at an acidic pH (ΦΔ = 0.69 at pH 5.0 at 635 nm) and could be deactivated at physiological pH (ΦΔ = 0.06 at pH 7.4 at 635 nm). The subcellular location-confined pH-activatable photosensitization at NIR region and the cancer cell-targeting feature led to excellent capability to selectively kill cancer cells and prevent the damage to normal cells, which greatly lowered the side effects. Through intravenous injection of FA-NMe2Se4N2 nanoparticles in tumor-bearing mice, tumor elimination was observed after NIR irradiation. This work presents a new paradigm for specific PDT against cancer and provides a new avenue for preparation of highly efficient photosensitizers.

H2O2-Activatable and O2-Evolving Nanoparticles for Highly Efficient and Selective Photodynamic Therapy against Hypoxic Tumor Cells

The low selectivity of currently available photosensitizers, which causes the treatment-related toxicity and side effects on adjacent normal tissues, is a major limitation for clinical photodynamic therapy (PDT) against cancer. Moreover, since PDT process is strongly oxygen dependent, its therapeutic effect is seriously hindered in hypoxic tumor cells. To overcome these problems, a cell-specific, H(2)O(2)-activatable, and O(2)-evolving PDT nanoparticle (HAOP NP) is developed for highly selective and efficient cancer treatment. The nanoparticle is composed of photosensitizer and catalase in the aqueous core, black hole quencher in the polymeric shell, and functionalized with a tumor targeting ligand c(RGDfK). Once HAOP NP is selectively taken up by α(v)β(3) integrin-rich tumor cells, the intracellular H(2)O(2) penetrates the shell into the core and is catalyzed by catalase to generate O(2), leading to the shell rupture and release of photosensitizer. Under irradiation, the released photosensitizer induces the formation of cytotoxic singlet oxygen ((1)O(2)) in the presence of O(2) to kill cancer cells. The cell-specific and H(2)O(2)-activatable generation of (1)O(2) selectively destroys cancer cells and prevents the damage to normal cells. More significantly, HAOP NP continuously generates O(2) in PDT process, which greatly improves the PDT efficacy in hypoxic tumor. Therefore, this work presents a new paradigm for H(2)O(2)-triggered PDT against cancer cells and provides a new avenue for overcoming hypoxia to achieve effective treatment of solid tumors.

A multifunctional nanomicelle for real-time targeted imaging and precise near-infrared cancer therapy

Simultaneous targeted cancer imaging, therapy and real-time therapeutic monitoring can prevent over- or undertreatment. This work describes the design of a multifunctional nanomicelle for recognition and precise near-infrared (NIR) cancer therapy. The nanomicelle encapsulates a new pH-activatable fluorescent probe and a robust NIR photosensitizer, R16FP, and is functionalized with a newly screened cancer-specific aptamer for targeting viable cancer cells. The fluorescent probe can light up the lysosomes for real-time imaging. Upon NIR irradiation, R16FP-mediated generation of reactive oxygen species causes lysosomal destruction and subsequently trigger lysosomal cell death. Meanwhile the fluorescent probe can reflect the cellular status and in situ visualize the treatment process. This protocol can provide molecular information for precise therapy and therapeutic monitoring.

A Highly Selective, Cell‐Permeable Fluorescent Nanoprobe for Ratiometric Detection and Imaging of Peroxynitrite in Living Cells

Peroxynitrite (ONOO(-)) is a highly reactive species implicated in the pathology of numerous diseases and there is currently great interest in developing fluorescent probes that can selectively detect ONOO(-) in living cells. Herein, a polymeric micelle-based and cell-penetrating peptide-coated fluorescent nanoprobe that incorporates ONOO(-) indicator dye and reference dye for the ratiometric detection and imaging of ONOO(-) has been developed. The nanoprobe effectively avoids the influences from enzymatic reaction and high-concentration ·OH and ClO(-). The improved ONOO(-) selectivity of the nanoprobe is achieved by a delicate complementarity of properties between the nanomatrix and the embedded molecular probe (BzSe-Cy). This nanoprobe also has other attractive properties, such as good water solubility, photostability, biocompatibility, and near-infrared excitation and emission. Fluorescence imaging experiments by confocal microscopy show that this nanoprobe is capable of visualizing ONOO(-) produced in living cells and it exhibits very low toxicity and good membrane permeability. We anticipate that this technique will be a potential tool for the precise pathological understanding and diagnosis of ONOO(-)-related human diseases.

Pegylated folate and peptide-decorated graphene oxide nanovehicle for in vivo targeted delivery of anticancer drugs and therapeutic self-monitoring

This work reports a graphene oxide-based nanovehicle with conjugation of pegylated folate for targeted delivery of anticancer drugs and fluorescein-labeled peptide for therapeutic self-monitoring in vitro and in vivo. The nanovehicle could absorb hydrophobic and aromatic drug molecules with high loading capacity and efficiency of more than 1.7 mg mg(-1) and 90%, respectively. MTT and flow cytometric assays demonstrated that the drug-loaded nanovehicle could specifically transport and release the drugs into the folate receptor high-expressed cancer cells, which ensured a high therapeutic efficiency to cancer cells and prevented the injury to normal cells. Moreover, confocal fluorescence imaging confirmed that the drug-induced cancer cell death could be visualized with the light-up fluorescence of fluorescein activated by caspase-3. The targeted delivery of drug and self-evaluation of therapeutic efficacy were further successfully realized by living imaging in tumor-bearing mice, which broaden the applications of this theranostic system in vivo and may offer new opportunities for precise cancer treatment.

Porphodilactones as Synthetic Chlorophylls: Relative Orientation of β-Substituents on a Pyrrolic Ring Tunes NIR Absorption

Porphodilactones represent the porphyrin analogues, in which the peripheral bonds of two pyrrole rings are replaced by lactone moieties. They provide an opportunity to investigate how β-substituent orientation of porphyrinoids modulates the electronic structures and optical properties, in a manner similar to what is observed with naturally occurring chlorophylls. In this work, a comprehensive description of the synthesis, characterization, and optical properties of meso-tetrakispentafluorophenylporphodilactone isomers is first reported. The β-dilactone moieties are found to lie at opposite pyrrole positions (trans- and cis-configurations are defined by the relative orientations of the carbonyl group when one lactone moiety is fixed), in accordance with earlier computational predictions (Gouterman, M. J. Am. Chem. Soc. 1989, 111, 3702). The relative orientation of the β-dilactone moieties has a significant influence on the electronic structures and photophysical properties. For example, the Qy band of trans-porphodilactone is red-shifted by 19 nm relative to that of the cis-isomer, and there is a 2-fold increase in the absorption intensity, which resembles the similar trends that have been reported for natural chlorophyll f and d. An in depth analysis of magnetic circular dichroism spectral data and TD-DFT calculations at the B3LYP/6-31G(d) level of theory demonstrates that the trans- and cis-orientations of the dilactone moieties have a significant effect on the relative energies of the frontier π-molecular orbitals. Importantly, the biological behaviors of the isomers reveal their different photocytotoxicity in NIR region (>650 nm). The influence of the relative orientation of the β-substituents on the optical properties in this context provides new insights into the electronic structures of porphyrinoids which could prove useful during the development of near-infrared absorbing photosensitizers.

How do nitrogen-doped carbon dots generate from molecular precursors? An investigation of the formation mechanism and a solution-based large-scale synthesis

A bottom-up method, using monoethanolamine (MEA) as both a passivation agent and a solvent, has been developed for rapid and massive synthesis of nitrogen-doped carbon dots (N-C-dots) from citric acid under heating conditions. This method requires a relatively mild temperature (170 °C) without special equipment, and affords one-pot large-scale production (39.96 g) of high-quality N-C-dots (quantum yield of 40.3%) in a few minutes (10 minutes). Significantly, an interesting formation process of N-C-dots, for the first time, has been monitored by transmission electron microscopy, ultraviolet-visible absorbance spectroscopy, photoluminescence spectroscopy, Fourier transformed infrared spectroscopy, and thermogravimetric analysis, and a corresponding formation mechanism, including polymerization, aromatization, nucleation, and growth, is proposed. It is important that the MEA-based synthesis of N-C-dots can be extended to various precursors, such as glucose, ascorbic acid, cysteine, and glutathione, which show general universality. Furthermore, the N-C-dots with strong fluorescence, excellent optical stability, and low cytotoxicity are successfully applied as fluorescent probes for bioimaging.

Folate Receptor-Targeted and Cathepsin B-Activatable Nanoprobe for In Situ Therapeutic Monitoring of Photosensitive Cell Death

The integration of diagnostic and therapeutic functions in a single system holds great promise to enhance the theranostic efficacy and prevent the under- or overtreatment. Herein, a folate receptor-targeted and cathepsin B-activatable nanoprobe is designed for background-free cancer imaging and selective therapy. The nanoprobe is prepared by noncovalently assembling phospholipid-poly(ethylene oxide) modified folate and photosensitizer-labeled peptide on the surface of graphene oxide. After selective uptake of the nanoprobe into lysosome of cancer cells via folate receptor-mediated endocytosis, the peptide can be cleaved to release the photosensitizer in the presence of cancer-associated cathepsin B, which leads to 18-fold fluorescence enhancement for cancer discrimination and specific detection of intracellular cathepsin B. Under irradiation, the released photosensitizer induces the formation of cytotoxic singlet oxygen for triggering photosensitive lysosomal cell death. After lysosomal destruction, the lighted photosensitizer diffuses from lysosome into cytoplasm, which provides a visible method for in situ monitoring of therapeutic efficacy. The nanoprobe exhibits negligible dark toxicity and high phototoxicity with the cell mortality rate of 0.06% and 72.1%, respectively, and the latter is specific to folate receptor-positive cancer cells. Therefore, this work provides a simple but powerful protocol with great potential in precise cancer imaging, therapy, and therapeutic monitoring.

A new aza-BODIPY based NIR region colorimetric and fluorescent chemodosimeter for fluoride

The synthesis and characterization of a novel NIR region fluoride sensor, that makes use of the aza-boron-dipyrromethene (aza-BODIPY) fluorophore, is described. An arylmagnesium bromide was formed by reacting 4-bromophenol with a tert-butyldimethylsilyl protecting group and magnesium, which was then used to prepare the aza-BODIPY through a reaction with phthalonitrile. The unusually strong affinity between the fluoride anion and silicon is used to create a sensor dye, which exhibits a highly specific, rapid colorimetric and ‘turn-off’ fluorescence response for F− in solution and in living HeLa cells. With F−, there is enhanced intramolecular charge transfer within the S1 state and this results in efficient nonradiative decay and hence in a marked decrease in fluorescence emission intensity.

Oxygen-driven, high-efficiency production of nitrogen-doped carbon dots from alkanolamines and their application for two-photon cellular imaging

A novel oxygen-driven method has been developed for low-cost, large-scale, and high-efficiency production of nitrogen-doped carbon dots (N-C-dots) by bubbling pure oxygen into monoethanolamine (MEA) under heating conditions. We find that the addition of pure oxygen significantly increases the reaction rate, and makes feasible one-pot gram scale fabrication (3.36 g) of highly photoluminescent N-C-dots in a couple of hours (2.0 h). With an instantaneous nucleation and gradual growth mechanism, precise control over the particle size of the N-C-dots from 2.0 to 16.1 nm is achieved by simply prolonging the heating time from 0.5 to 4.0 h. The as-prepared N-C-dots contain aromatic CN heterocycles in the core and have plentiful hydrophilic groups on the surface. Practically, the oxygen-driven method can be used to synthesize fluorescent N-C-dots from other alkanolamines such as diethanolamine (DEA) and triethanolamine (TEA), which shows general universality. Due to the strong up-conversion photoluminescence, good aqueous dispersibility, high photostability, excellent biocompatibility, and low cytotoxicity, the N-C-dots are demonstrated to be promising two-photon probes for high contrast bioimaging applications.