Specific Generation of Singlet Oxygen through the Russell Mechanism in Hypoxic Tumors and GSH Depletion by Cu‐TCPP Nanosheets for Cancer Therapy

The generation of singlet oxygen (¹O₂) during photodynamic therapy is limited by the precise cooperation of light, photosensitizer, and oxygen, and the therapeutic efficiency is restricted by the elevated glutathione (GSH) levels in cancer cells. Herein, we report that an ultrathin two‐dimensional metal–organic framework of Cu‐TCPP nanosheets (TCPP=tetrakis(4‐carboxyphenyl)porphyrin) can selectively generate ¹O₂ in a tumor microenvironment. This process is based on the peroxidation of the TCPP ligand by acidic H₂O₂ followed by reduction to peroxyl radicals under the action of the peroxidase‐like nanosheets and Cu²⁺, and their spontaneous recombination reaction by the Russell mechanism. In addition, the nanosheets can also deplete GSH. Consequently, the Cu‐TCPP nanosheets can selectively destroy tumor cells with high efficiency, constituting an attractive way to overcome current limitations of photodynamic therapy.     

A Phototheranostic Strategy to Continuously Deliver Singlet Oxygen in the Dark and Hypoxic Tumor Microenvironment

Continuous irradiation during photodynamic therapy (PDT) inevitably induces tumor hypoxia, thereby weakening the PDT effect. In PDT‐induced hypoxia, providing singlet oxygen from stored chemical energy may enhance the cell‐killing effect and boost the therapeutic effect. Herein, we present a phototheranostic (DPPTPE@PEG‐Py NPs) prepared by using a 2‐pyridone‐based diblock polymer (PEG‐Py) to encapsulate a semiconducting, heavy‐atom‐free pyrrolopyrrolidone‐tetraphenylethylene (DPPTPE) with high singlet‐oxygen‐generation ability both in dichloromethane and water. The PEG‐Py can trap the ¹O₂ generated from DPPTPE under laser irradiation and form a stable intermediate of endoperoxide, which can then release ¹O₂ in the dark, hypoxic tumor microenvironment. Furthermore, fluorescence‐imaging‐guided phototherapy demonstrates that this phototheranostic could completely inhibit tumor growth with the help of laser irradiation.     

Controllable Synthesis of Porphyrin‐Based 2D Lanthanide Metal–Organic Frameworks with Thickness‐ and Metal‐Node‐Dependent Photocatalytic Performance

Synthesizing 2D metal–organic frameworks (2D MOFs) in high yields and rational tailoring of the properties in a predictable manner for specific applications is extremely challenging. Now, a series of porphyrin‐based 2D lanthanide MOFs (Ln‐TCPP, Ln=Ce, Sm, Eu, Tb, Yb, TCPP=tetrakis(4‐carboxyphenyl) porphyrin) with different thickness were successfully prepared in a household microwave oven. The as‐prepared 2D Ln‐TCPP nanosheets showed thickness‐dependent photocatalytic performances towards photooxidation of 1,5‐dihydroxynaphthalene (1,5‐DHN) to synthesize juglone. Particularly, the Yb‐TCPP displayed outstanding photodynamic activity to generate O₂^? and ¹O₂. This work not only provides fundamental insights into structure designing and property tailoring of 2D MOFs nanosheets, but also pave a new way to improve the photocatalytic performance.     

Facile synthesis and in vivo bioimaging applications of porphyrin derivative-encapsulated polymer nanoparticles

Fluorescence (FL) imaging guided photodynamic therapy (PDT) is becoming highly desirable for personalized therapy and precision medicine. In this study, fluorescent polymer nanoparticles TCPP@PEI/PGA were facilely synthesized through electrostatic interaction-mediated self-assembly of porphyrins tetra(4-carboxyphenyl)porphine (TCPP) and polyethylenimine (PEI), and subsequent surface modification with γ-poly(glutamic acid) (γ-PGA). TCPP served a dual function as the FL imaging probe and the photosensitizer. The as-prepared TCPP@PEI/PGA nanoparticles showed excellent water-solubility and biocompatibility, while having outstanding capabilities of in vivo bioimaging and ¹O₂ generation. FL bioimaging of mice and effective killing of CT 26 cells as well as CT 26 tumor-bearing mice upon laser irradiation were successfully demonstrated when using TCPP@PEI/PGA as theranostic nanoprobes. This study provides a simple but robust method to design and synthesize porphyrin-based polymer nanoparticles for theranostics.     

Self‐Amplified Photodynamic Therapy through the 1O2‐Mediated Internalization of Photosensitizers from a Ppa‐Bearing Block Copolymer

Nanocarriers are employed to deliver photosensitizers for photodynamic therapy (PDT) through the enhanced penetration and retention effect, but disadvantages including the premature leakage and non‐selective release of photosensitizers still exist. Herein, we report a ¹O₂‐responsive block copolymer (POEGMA‐b‐P(MAA‐co‐VSPpaMA) to enhance PDT via the controllable release of photosensitizers. Once nanoparticles formed by the block copolymer have accumulated in a tumor and have been taken up by cancer cells, pyropheophorbide a (Ppa) could be controllably released by singlet oxygen (¹O₂) generated by light irradiation, enhancing the photosensitization. This was demonstrated by confocal laser scanning microscopy and in vivo fluorescence imaging. The ¹O₂‐responsiveness of POEGMA‐b‐P(MAA‐co‐VSPpaMA) block copolymer enabled the realization of self‐amplified photodynamic therapy by the regulation of Ppa release using NIR illumination. This may provide a new insight into the design of precise PDT.     

激光诱导的亚硝酸与二苯醚的反应机理

355 nm光照下利用瞬态吸收光谱技术进行了有氧、无氧条件下二苯醚与亚硝酸体系的反应机理研究, 考察了其中瞬态物种的衰减行为, 并对其光解产物进行了GC-MS分析. 研究表明, HNO₂在355 nm紫外光的照射下产生的OH自由基和二苯醚反应生成C₁₂H₁₀O-OH 加合物, N₂条件下C₁₂H₁₀O-OH衰减的速率常数为(1.86±0.14)×10⁵ s^－1, 在有氧条件下, C₁₂H₁₀O-OH可转化为C₁₂H₁₀O-OHO₂, 衰减的速率常数为(6.6±0.4)×10⁶ s^－1. N₂条件下最终产物为苯酚、2-羟基二苯醚、4-羟基二苯醚、4-硝基二苯醚.     

Photosynthetic Tumor Oxygenation by Photosensitizer-Containing Cyanobacteria for Enhanced Photodynamic Therapy

Sustained tumor oxygenation is of critical importance during type-II photodynamic therapy (PDT), which depends on the intratumoral oxygen level for the generation of reactive oxygen species. Herein, the modification of photosynthetic cyanobacteria with the photosensitizer chlorin e6 (ce6) to form ce6-integrated photosensitive cells, termed ceCyan, is reported. Upon 660 nm laser irradiation, sustained photosynthetic O₂ evolution by the cyanobacteria and the immediate generation of reactive singlet oxygen species (¹O₂) by the integrated photosensitizer could be almost simultaneously achieved for tumor therapy using type-II PDT both in vitro and in vivo. This work contributes a conceptual while practical paradigm for biocompatible and effective PDT using hybrid microorganisms, displaying a bright future in clinical PDT by microbiotic nanomedicine.     

Controlled Generation of Singlet Oxygen in Living Cells with Tunable Ratios of the Photochromic Switch in Metal–Organic Frameworks

Development of a photosensitizing system that can reversibly control the generation of singlet oxygen (¹O₂) is of great interest for photodynamic therapy (PDT). Recently several photosensitizer–photochromic‐switch dyads were reported as a potential means of the ¹O₂ control in PDT. However, the delivery of such a homogeneous molecular dyad as designed (e.g., optimal molar ratio) is extremely challenging in living systems. Herein we show a Zr‐MOF nanoplatform, demonstrating energy transfer‐based ¹O₂ controlled PDT. Our strategy allows for tuning the ratios between photosensitizer and the switch molecule, enabling maximum control of ¹O₂ generation. Meanwhile, the MOF provides proximal placement of the functional entities for efficient intermolecular energy transfer. As a result, the MOF nanoparticle formulation showed enhanced PDT efficacy with superior ¹O₂ control compared to that of homogeneous molecular analogues.     

A Comparison of Dose Metrics to Predict Local Tumor Control for Photofrin‐mediated Photodynamic Therapy

This preclinical study examines light fluence, photodynamic therapy (PDT) dose and “apparent reacted singlet oxygen,” [¹O₂]_rx, to predict local control rate (LCR) for Photofrin‐mediated PDT of radiation‐induced fibrosarcoma (RIF) tumors. Mice bearing RIF tumors were treated with in‐air fluences (50–250 J cm^?2) and in‐air fluence rates (50–150 mW cm^?2) at Photofrin dosages of 5 and 15 mg kg^?1 and a drug‐light interval of 24 h using a 630‐nm, 1‐cm‐diameter collimated laser. A macroscopic model was used to calculate [¹O₂]_rx and PDT dose based on in vivo explicit dosimetry of the drug concentration, light fluence and tissue optical properties. PDT dose and [¹O₂]_rx were defined as a temporal integral of drug concentration and fluence rate, and singlet oxygen concentration consumed divided by the singlet oxygen lifetime, respectively. LCR was stratified for different dose metrics for 74 mice (66 + 8 control). Complete tumor control at 14 days was observed for [¹O₂]_rx ≥ 1.1 mm or PDT dose ≥1200 μm J cm^?2 but cannot be predicted with fluence alone. LCR increases with increasing [¹O₂]_rx and PDT dose but is not well correlated with fluence. Comparing dosimetric quantities, [¹O₂]_rx outperformed both PDT dose and fluence in predicting tumor response and correlating with LCR.     

Photophysics of Silicon Phthalocyanines in Aqueous Media

Phthalocyanines have been used as photodynamic therapy (PDT) agents because of their uniquely favorable optical properties and high photostability. They have been shown to be highly successful for the treatment of cancer through efficient singlet‐oxygen (¹O₂) production. However, due to their hydrophobic properties, the considerations of solubility and cellular location have made understanding their photophysics in vitro and in vivo difficult. Indeed, many quantitative assessments of PDT reagents are undertaken in purely organic solvents, presenting challenges for interpreting observations during practical application in vivo. With steady‐state and time‐resolved laser spectroscopy, we show that for axial ligated silicon phthalocyanines in aqueous media, both the water:lipophile ratio and the pH have drastic effects on their photophysics, and ultimately dictate their functionality as PDT drugs. We suggest that considering the presented photophysics for PDT drugs in aqueous solutions leads to guidelines for a next generation of even more potent PDT agents.     

Photosynthetic Tumor Oxygenation by Photosensitizer‐Containing Cyanobacteria for Enhanced Photodynamic Therapy

Sustained tumor oxygenation is of critical importance during type‐II photodynamic therapy (PDT), which depends on the intratumoral oxygen level for the generation of reactive oxygen species. Herein, the modification of photosynthetic cyanobacteria with the photosensitizer chlorin e6 (ce6) to form ce6‐integrated photosensitive cells, termed ceCyan, is reported. Upon 660 nm laser irradiation, sustained photosynthetic O₂ evolution by the cyanobacteria and the immediate generation of reactive singlet oxygen species (¹O₂) by the integrated photosensitizer could be almost simultaneously achieved for tumor therapy using type‐II PDT both in vitro and in vivo. This work contributes a conceptual while practical paradigm for biocompatible and effective PDT using hybrid microorganisms, displaying a bright future in clinical PDT by microbiotic nanomedicine.     

A Highly Efficient Chemiluminescence Probe for the Detection of Singlet Oxygen in Living Cells

Singlet oxygen is among the reactive oxygen species (ROS) with the shortest life‐times in aqueous media because of its extremely high reactivity. Therefore, designing sensors for detection of ¹O₂ is perhaps one of the most challenging tasks in the field of molecular probes. Herein, we report a highly selective and sensitive chemiluminescence probe ( SOCL‐CPP ) for the detection of ¹O₂ in living cells. The probe reacts with ¹O₂ to form a dioxetane that spontaneously decomposes under physiological conditions through a chemiexcitation pathway to emit green light with extraordinary intensity. SOCL‐CPP demonstrated promising ability to detect and image intracellular ¹O₂ produced by a photosensitizer in HeLa cells during photodynamic therapy (PDT) mode of action. Our findings make SOCL‐CPP the most effective known chemiluminescence probe for the detection of ¹O₂. We anticipate that our chemiluminescence probe for ¹O₂ imaging would be useful in PDT‐related applications and for monitoring ¹O₂ endogenously generated by cells in response to different stimuli.     

An Iridium Complex as an AIE-active Photosensitizer for Image-guided Photodynamic Therapy

Image-guided photodynamic therapy (PDT) has received growing attention due to its non-invasiveness and precise controllability. However, the PDT efficiency of most photosensitizers are decreased in living system due to the aggregation-caused singlet oxygen (¹O₂) generation decreasing. Herein, we present an Iridium (III) pyridylpyrrole complex (Ir-1) featuring of aggregation-induced emission (AIE) and ¹O₂ generation characteristics for image-guided PDT of cancer. Ir-1 aqueous solution exhibits bright red phosphorescence peaked at 630 nm, large Stokes shift of 227 nm, and good ¹O₂ generation ability. The ¹O₂ generating rate of Ir-1 in EtOH/water mixture solution is 2.3 times higher than that of Rose Bengal. In vitro experimental results revealed that Ir-1 has better biocompatibility and higher phototoxicity compared with clinically used photosensitizers (Rose Bengal and Ce6), suggesting that Ir-1 can serve as a photosensitizer for image-guided PDT of cancer.     

Double‐Oxygen‐Atom Transfer in Reactions of CemO2m+ (m=2–6) with C2H2

Cerium oxide cluster cations (Ce_mO_n⁺, m=2–16; n=2m, 2m±1 and 2m±2) are prepared by laser ablation and reacted with acetylene (C₂H₂) in a fast‐flow reactor. A time‐of‐flight mass spectrometer is used to detect the cluster distribution before and after the reactions. Reactions of stoichiometric Ce_mO_2m⁺ (m=2–6) with C₂H₂ produce Ce_mO_2m?2⁺ clusters, which indicates a “double‐oxygen‐atom transfer” reaction Ce_mO_2m⁺+C₂H₂→Ce_mO_2m?2⁺+(CHO)₂ (ethanedial). A single‐oxygen‐atom transfer reaction channel is also identified as Ce_mO_2m⁺+C₂H₂→Ce_mO_2m?1⁺+C₂H₂O (at least for m=2 and 3). Density functional theory calculations are performed to study reaction mechanisms of Ce₂O₄⁺+C₂H₂, and the calculated results confirm that both the single‐ and double‐oxygen‐atom transfer channels are thermodynamically and kinetically favourable.     

Hypocrellin B doped and pH-responsive silica nanoparticles for photodynamic therapy

pH-responsive ¹O₂ photosensitizing systems may serve as selective photodynamic therapy (PDT) agents by targeting the acidic interstitial fluid of many kinds of tumors. In this work, a natural and clinically used photosensitizer (Hypocrellin B, HB) and a pH indicator (Bromocresol Purple, BCP) were co-encapsulated in organically modified silica nanoparticles. BCP successfully regulated the ¹O₂ generation efficiency of HB through the “inner filter” effect, which shows much stronger ¹O₂ generation ability in an acidic than in a basic environment. In vitro experiments also demonstrated that HB-doped nanoparticles are effective in killing tumor cells by PDT.

     

A Targeting Singlet Oxygen Battery for Multidrug-Resistant Bacterial Deep-Tissue Infections

Traditional photodynamic therapy (PDT) is dependent on externally applied light and oxygen, and the depth of penetration of these factors can be insufficient for the treatment of deep infections. The short half-life and short diffusion distance of reactive oxygen species (ROS) also limit the antibacterial efficiency of PDT. Herein, we designed a targeting singlet oxygen delivery system, CARG-Py, for irradiation-free and oxygen-free PDT. This system was converted to the “singlet oxygen battery” CARG-¹O₂ and released singlet oxygen without external irradiation or oxygen. CARG-¹O₂ is composed of pyridones coupled to a targeting peptide that improves the utilization of singlet oxygen in deep multidrug-resistant bacterial infections. CARG-¹O₂ was shown to damage DNA, protein, and membranes by increasing the level of reactive oxygen inside bacteria; the attacking of multiple biomolecular sites caused the death of methicillin-resistant Staphylococcus aureus (MRSA). An in vivo study in a MRSA-infected mouse model of pneumonia demonstrated the potential of CARG-¹O₂ for the efficient treatment of deep infections. This work provides a new strategy to improve traditional PDT for irradiation- and oxygen-free treatment of deep infections while improving convenience of PDT.     

Hydrogen Peroxide Enhances the Antibacterial Effect of Methylene Blue‐based Photodynamic Therapy on Biofilm‐forming Bacteria

Recently, increased attention has been focused on endoscopic disinfection after outbreaks of drug‐resistant infections associated with gastrointestinal endoscopy. The aims of this study were to investigate the bactericidal efficacy of methylene blue (MB)‐based photodynamic therapy (PDT) on Pseudomonas aeruginosa (P. aeruginosa), which is the major cause of drug‐resistant postendoscopy outbreak, and to assess the synergistic effects of hydrogen peroxide addition to MB‐based PDT on biofilms. In planktonic state of P. aeruginosa, the maximum decrease was 3 log₁₀ and 5.5 log₁₀ at 20 and 30 J cm^?2, respectively, following MB‐based PDT. However, the maximum reduction of colony forming unit (CFU) was decreased by 2.5 log₁₀ and 3 log₁₀ irradiation on biofilms. The biofilm formation was significantly inhibited upon irradiation with MB‐based PDT. When the biofilm state of P. aeruginosa was treated with MB‐based PDT with hydrogen peroxide, the CFU was significantly decreased by 6 log₁₀ after 20 J cm^?2, by 7 log₁₀ after 30 J cm^?2 irradiation, suggesting significantly higher efficacy than MB‐based PDT alone. The implementation of the combination of hydrogen peroxide with MB‐based PDT through working channels might be appropriate for preventing early colonization and biofilm formation in the endoscope and postendoscopy outbreak.     

Measurement of Intracellular Oxygen Concentration During Photodynamic Therapy in vitro

A technique is introduced that monitors the depletion of intracellular ground state oxygen concentration ([³O₂]) during photodynamic therapy of Mat‐LyLu cell monolayers and cell suspensions. The photosensitizer Pd(II) meso‐tetra(4‐carboxyphenyl)porphine (PdT790) is used to manipulate and indicate intracellular [³O₂] in both of the in vitro models. The Stern–Volmer relationship for PdT790 phosphorescence was characterized in suspensions by flowing nitrogen over the suspension while short pulses of 405 nm light were used to excite the sensitizer. The bleaching of sensitizer and the oxygen consumption rate were also measured during continuous exposure of the cell suspension to the 405 nm laser. Photodynamic therapy (PDT) was conducted in both cell suspensions and in cell monolayers under different treatment conditions while the phosphorescence signal was acquired. The intracellular [³O₂] during PDT was calculated by using the measured Stern–Volmer relationship and correcting for sensitizer photobleaching. In addition, the amount of oxygen that was consumed during the treatments was calculated. It was found that even at large oxygen consumption rates, cells remain well oxygenated during PDT of cell suspensions. For monolayer treatments, it was found that intracellular [³O₂] is rapidly depleted over the course of PDT.     

A stable pillared metal–organic framework constructed by H4TCPP ligand as luminescent sensor for selective detection of TNP and Fe3+ ions

A novel luminescent metal–organic framework ( Zn‐TCPP/BPY ) with pillared structure based on 2,3,5,6‐tetrakis(4‐carboxyphenyl)pyrazine (H₄TCPP) and 4,4′‐bipyridine (BPY) has been designed and synthesized through a solvothermal reaction. The [Zn₂(COO)₄] paddlewheel units are linked by TCPP^4? ligands to form two‐dimensional layers and further connected by BPY ligands as pillars to construct the twofold interpenetrating three‐dimensional framework. Interestingly, Zn‐TCPP/BPY possesses outstanding stability in organic solvents and water as well as maintains its structural rigidity in aqueous solutions of different pH values (3–12). After activation, Zn‐TCPP/BPY possesses permanent porosity with Brunauer–Emmett–Teller surface area of 630 m² g^–1. Remarkably, Zn‐TCPP/BPY displays excellent fluorescent property in virtue of the aggregation‐induced emission effect of the H₄TCPP ligand, which can be highly active and quenched by small amounts of 2,4,6‐trinitrophenol (TNP) and Fe³⁺ ions. Furthermore, the detection effect of Zn‐TCPP/BPY remains basically the same even after five cycles. The excellent stability, high sensitivity, and recyclability of Zn‐TCPP/BPY make it an outstanding chemical sensor for detecting TNP and Fe³⁺ ions.     

Self-Amplified Photodynamic Therapy through the 1O2-Mediated Internalization of Photosensitizers from a Ppa-Bearing Block Copolymer

Nanocarriers are employed to deliver photosensitizers for photodynamic therapy (PDT) through the enhanced penetration and retention effect, but disadvantages including the premature leakage and non-selective release of photosensitizers still exist. Herein, we report a ¹O₂-responsive block copolymer (POEGMA-b-P(MAA-co-VSPpaMA) to enhance PDT via the controllable release of photosensitizers. Once nanoparticles formed by the block copolymer have accumulated in a tumor and have been taken up by cancer cells, pyropheophorbide a (Ppa) could be controllably released by singlet oxygen (¹O₂) generated by light irradiation, enhancing the photosensitization. This was demonstrated by confocal laser scanning microscopy and in vivo fluorescence imaging. The ¹O₂-responsiveness of POEGMA-b-P(MAA-co-VSPpaMA) block copolymer enabled the realization of self-amplified photodynamic therapy by the regulation of Ppa release using NIR illumination. This may provide a new insight into the design of precise PDT.