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.     

Enhanced Photodynamic Therapy by Reduced Levels of Intracellular Glutathione Obtained By Employing a Nano‐MOF with CuII as the Active Center

In photodynamic therapy (PDT), the level of reactive oxygen species (ROS) produced in the cell directly determines the therapeutic effect. Improvement in ROS concentration can be realized by reducing the glutathione (GSH) level or increasing the amount of photosensitizer. However, excessive amounts photosensitizer may cause side effects. Therefore, the development of photosensitizers that reduce GSH levels through synergistically improving ROS concentration in order to strengthen the efficacy of PDT for tumor is important. We report a nano‐metal–organic framework (Cu^II‐metalated nano‐MOF {CuL‐[AlOH]₂}_n (MOF‐2, H₆L=mesotetrakis(4‐carboxylphenyl)porphyrin)) based on Cu^II as the active center for PDT. This MOF‐2 is readily taken up by breast cancer cells, and high levels of ROS are generated under light irradiation. Meanwhile, intracellular GSH is considerably decreased owing to absorption on MOF‐2; this synergistically increases ROS concentration and accelerates apoptosis, thereby enhancing the effect of PDT. Notably, based on the direct adsorption of GSH, MOF‐2 showed a comparable effect with the commercial antitumor drug camptothecin in a mouse breast cancer model. This work provides strong evidence for MOF‐2 as a promising new PDT candidate and anticancer drug.     

GSH and H2O2 Co‐Activatable Mitochondria‐Targeted Photodynamic Therapy under Normoxia and Hypoxia

Currently, photosensitizers (PSs) that are microenvironment responsive and hypoxia active are scarcely available and urgently desired for antitumor photodynamic therapy (PDT). Presented herein is the design of a redox stimuli activatable metal‐free photosensitizer (aPS), also functioning as a pre‐photosensitizer as it is converted to a PS by the mutual presence of glutathione (GSH) and hydrogen peroxide (H₂O₂) with high specificity on a basis of domino reactions on the benzothiadiazole ring. Superior to traditional PSs, the activated aPS contributed to efficient generation of reactive oxygen species including singlet oxygen and superoxide ion through both type 1 and type 2 pathways, alleviating the aerobic requirement for PDT. Equipped with a triphenylphosphine ligand for mitochondria targeting, ^mito aPS showed excellent phototoxicity to tumor cells with low light fluence under both normoxic and hypoxic conditions, after activation by intracellular GSH and H₂O₂. The ^mito aPS was also compatible to near infrared PDT with two photon excitation (800 nm) for extensive bioapplications.     

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.     

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.     

Structural Transformation in Metal–Organic Frameworks for Reversible Binding of Oxygen

Polycyclic aromatic derivatives can trap ¹O₂ to form endoperoxides (EPOs) for O₂ storage and as sources of reactive oxygen species. However, these materials suffer from structural amorphism, which limit both practical applications and fundamental studies on their structural optimization for O₂ capture and release. Metal–organic frameworks (MOFs) offer advantages in O₂ binding, such as clear structure–performance relationships and precise controllability. Herein, we report the reversible binding of O₂ is realized via the chemical transformation between anthracene‐based and the corresponding EPO‐based MOF. It is shown that anthracene‐based MOF, the framework featuring linkers with polycyclic aromatic structure, can rapidly trap ¹O₂ to form EPOs and can be restored upon UV irradiation or heating to release O₂. Furthermore, we confirm that photosensitizer‐incorporated anthracene‐based MOF are promising candidates for reversible O₂ carriers controlled by switching Vis/UV irradiation.     

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.     

Effect and Mechanism of a New Photodynamic Therapy with Glycoconjugated Fullerene

When irradiated, fullerene efficiently generates reactive oxygen species (ROS) and is an attractive photosensitizer for photodynamic therapy (PDT). Ideally, photosensitizers for PDT should be water-soluble and tumor-specific. Because cancer cells endocytose glucose more effectively than normal cells, the characteristics of fullerene as a photosensitizer were improved by combining it with glucose. The cytotoxicity of PDT was studied in several cancer cell lines cultured with C₆₀-(Glc)1 (d -glucose residue pendant fullerene) and C₆₀-(6Glc)1 (a maltohexaose residue pendant fullerene) subsequently irradiated with UVA₁. PDT alone induced significant cytotoxicity. In contrast, PDT with the glycoconjugated fullerene exhibited no significant cytotoxicity against normal fibroblasts, indicating that PDT with these compounds targeted cancer cells. To investigate whether the effects of PDT with glycoconjugated fullerene were because of the generation of singlet oxygen (¹O₂), NaN₃ was added to cancer cells during irradiation. NaN₃ extensively blocked PDT-induced apoptosis, suggesting that PDT-induced cell death was a result of the generation of ¹O₂. Finally, to investigate the effect of PDT in vivo, melanoma-bearing mice were injected intratumorally with C₆₀-(Glc)1 and irradiated with UVA₁. PDT with C₆₀-(Glc)1 suppressed tumor growth. These findings indicate that PDT with glycoconjugated fullerene exhibits tumor-specific cytotoxicity both in vivo and in vitro via the induction of ¹O₂.     

Photodynamic Therapy Efficacy Enhanced by Dynamics: The Role of Charge Transfer and Photostability in the Selection of Photosensitizers

Progress in the photodynamic therapy (PDT) of cancer should benefit from a rationale to predict the most efficient of a series of photosensitizers that strongly absorb light in the phototherapeutic window (650–800 nm) and efficiently generate reactive oxygen species (ROS=singlet oxygen and oxygen‐centered radicals). We show that the ratios between the triplet photosensitizer–O₂ interaction rate constant (k_D) and the photosensitizer decomposition rate constant (k_d), k_D/k_d, determine the relative photodynamic activities of photosensitizers against various cancer cells. The same efficacy trend is observed in vivo with DBA/2 mice bearing S91 melanoma tumors. The PDT efficacy intimately depends on the dynamics of photosensitizer–oxygen interactions: charge transfer to molecular oxygen with generation of both singlet oxygen and superoxide ion (high k_D) must be tempered by photostability (low k_d). These properties depend on the oxidation potential of the photosensitizer and are suitably combined in a new fluorinated sulfonamide bacteriochlorin, motivated by the rationale.     

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.

     

Photochromic Metal–Organic Frameworks: Reversible Control of Singlet Oxygen Generation

The controlled generation of singlet oxygen is of great interest owing to its potential applications including industrial wastewater treatment, photochemistry, and photodynamic therapy. Two photochromic metal–organic frameworks, PC‐PCN and SO‐PCN, have been developed. A photochromic reaction has been successfully realized in PC‐PCN while maintaining its single crystallinity. In particular, as a solid‐state material which inherently integrates the photochromic switch and photosensitizer, SO‐PCN has demonstrated reversible control of ¹O₂ generation. Additionally, SO‐PCN shows catalytic activity towards photooxidation of 1,5‐dihydroxynaphthalene.     

Activatable Singlet Oxygen Generation from Lipid Hydroperoxide Nanoparticles for Cancer Therapy

Reactive oxygen species (ROS)-induced apoptosis is a widely practiced strategy for cancer therapy. Although photodynamic therapy (PDT) takes advantage of the spatial–temporal control of ROS generation, the meticulous participation of light, photosensitizer, and oxygen greatly hinders the broad application of PDT as a first-line cancer treatment option. An activatable system has been developed that enables tumor-specific singlet oxygen (¹O₂) generation for cancer therapy, based on a Fenton-like reaction between linoleic acid hydroperoxide (LAHP) tethered on iron oxide nanoparticles (IO NPs) and the released iron(II) ions from IO NPs under acidic-pH condition. The IO-LAHP NPs are able to induce efficient apoptotic cancer cell death both in vitro and in vivo through tumor-specific ¹O₂ generation and subsequent ROS mediated mechanism. This study demonstrates the effectiveness of modulating biochemical reactions as a ROS source to exert cancer death.     

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.     

H2S‐Activable MOF Nanoparticle Photosensitizer for Effective Photodynamic Therapy against Cancer with Controllable Singlet‐Oxygen Release

Photodynamic therapy (PDT) has emerged as an important minimally invasive tumor treatment technology. The search for an effective photosensitizer to realize selective cancer treatment has become one of the major foci in recent developments of PDT technology. Controllable singlet‐oxygen release based on specific cancer‐associated events, as another major layer of selectivity mode, has attracted great attention in recent years. Here, for the first time, we demonstrated that a novel mixed‐metal metal–organic framework nanoparticle (MOF NP) photosensitizer can be activated by a hydrogen sulfide (H₂S) signaling molecule in a specific tumor microenvironment for PDT against cancer with controllable singlet‐oxygen release in living cells. The effective removal of tumors in vivo further confirmed the satisfactory treatment effect of the MOF NP photosensitizer.     

Two‐Dimensional Metal–Organic Framework Nanosheets for Membrane‐Based Gas Separation

Metal–organic framework (MOF) nanosheets could serve as ideal building blocks of molecular sieve membranes owing to their structural diversity and minimized mass‐transfer barrier. To date, discovery of appropriate MOF nanosheets and facile fabrication of high performance MOF nanosheet‐based membranes remain as great challenges. A modified soft‐physical exfoliation method was used to disintegrate a lamellar amphiprotic MOF into nanosheets with a high aspect ratio. Consequently sub‐10 nm‐thick ultrathin membranes were successfully prepared, and these demonstrated a remarkable H₂/CO₂ separation performance, with a separation factor of up to 166 and H₂ permeance of up to 8×10⁻⁷ mol m⁻² s⁻¹ Pa⁻¹ at elevated testing temperatures owing to a well‐defined size‐exclusion effect. This nanosheet‐based membrane holds great promise as the next generation of ultrapermeable gas separation membrane.     

Universal Scaffold for an Activatable Photosensitizer with Completely Inhibited Photosensitivity

Activatable photosensitizers (aPSs) sensitive to specific stimuli hold potential for targeting multiple disease biomarkers and are desirable for photodynamic therapy (PDT). Presented herein is the design of aPSs that can be activated and fully recover from an inhibited state in the presence of specific biomarker. A designed long‐wavelength D‐π‐A photosensitizer, PS_Se‐I , with highly efficient photosensitivity for generation of ¹O₂ was used. Caging of the phenolate donor of PS_Se‐I with a biomarker‐sensitive group provided ^ALP PS , and the drastic activation of its photosensitivity was demonstrated intracellularly. To enhance the flexibility of the design strategy, a clickable azide group was introduced into the scaffold to allow integration of more functionality. Modularly derived ^mito‐PN PS , equipped with a mitochondria‐targeting group and a specific peroxynitrite‐reactive trigger, was synthesized and demonstrated superior performance in cells. This strategy could lead to customization of aPSs applicable to a specific PDT.     

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.     

Intracellular Modulation of Excited‐State Dynamics in a Chromophore Dyad: Differential Enhancement of Photocytotoxicity Targeting Cancer Cells

The photosensitized generation of reactive oxygen species, and particularly of singlet oxygen [O₂(a¹Δ_g)], is the essence of photodynamic action exploited in photodynamic therapy. The ability to switch singlet oxygen generation on/off would be highly valuable, especially when it is linked to a cancer‐related cellular parameter. Building on recent findings related to intersystem crossing efficiency, we designed a dimeric BODIPY dye with reduced symmetry, which is ineffective as a photosensitizer unless it is activated by a reaction with intracellular glutathione (GSH). The reaction alters the properties of both the ground and excited states, consequently enabling the efficient generation of singlet oxygen. Remarkably, the designed photosensitizer can discriminate between different concentrations of GSH in normal and cancer cells and thus remains inefficient as a photosensitizer inside a normal cell while being transformed into a lethal singlet oxygen source in cancer cells. This is the first demonstration of such a difference in the intracellular activity of a photosensitizer.     

A pH-activatable and aniline-substituted photosensitizer for near-infrared cancer theranostics

This work reports a newly designed pH-activatable and aniline-substituted aza-boron-dipyrromethene as a trifunctional photosensitizer to achieve highly selective tumor imaging, efficient photodynamic therapy (PDT) and therapeutic self-monitoring through encapsulation in a cRGD-functionalized nanomicelle. The diethylaminophenyl is introduced in to the structure for pH-activatable near-infrared fluorescence and singlet oxygen (¹O₂) generation, and bromophenyl is imported to increase the ¹O₂ generation efficiency upon pH activation by virtue of its heavy atom effect. After encapsulation, the nanoprobe can target α_vβ₃ integrin-rich tumor cells via cRGD and is activated by physiologically acidic pH for cancer discrimination and PDT. The fascinating advantage of the nanoprobe is near-infrared implementation beyond 800 nm, which significantly improves the imaging sensitivity and increases the penetration depth of the PDT. By monitoring the fluorescence decrease in the tumor region after PDT, the therapeutic efficacy is demonstrated in situ and in real time, which provides a valuable and convenient self-feedback function for PDT efficacy tracking. Therefore, this rationally designed and carefully engineered nanoprobe offers a new paradigm for precise tumor theranostics and may provide novel opportunities for future clinical cancer treatment.     

介孔钛纳米复合团簇应用于光热-光动力疗法

在本文,采用水热法合成了一种新型的介孔二氧化钛/碳/亚甲蓝复合纳米团簇(TiO₂@C-MB),并应用于肿瘤细胞的光动力(PDT)和光热治疗(PTT)。系统中介孔二氧化钛作为有效的光敏剂,MB作为重要的光敏添加剂以改善二氧化钛纳米晶的光化学效应,并将其光响应区域拓宽至光动力学疗法的理想治疗窗(650~900 nm)。柠檬酸在水热条件下被还原成碳并裹覆在二氧化钛表面。碳层表现出良好的光热效果,也充当多功能的电子受体以加速生成单线态氧。该纳米团簇不仅可以保持肿瘤细胞内部高浓度的MB和二氧化钛以产生大量的单线态氧杀死肿瘤细胞,而且可以避免MB退化失活。