Nanoscale Metal–Organic Layers for Deeply Penetrating X‐ray‐Induced Photodynamic Therapy

We report the rational design of metal–organic layers (MOLs) that are built from [Hf₆O₄(OH)₄(HCO₂)₆] secondary building units (SBUs) and Ir[bpy(ppy)₂]⁺‐ or [Ru(bpy)₃]²⁺‐derived tricarboxylate ligands (Hf‐BPY‐Ir or Hf‐BPY‐Ru; bpy=2,2′‐bipyridine, ppy=2‐phenylpyridine) and their applications in X‐ray‐induced photodynamic therapy (X‐PDT) of colon cancer. Heavy Hf atoms in the SBUs efficiently absorb X‐rays and transfer energy to Ir[bpy(ppy)₂]⁺ or [Ru(bpy)₃]²⁺ moieties to induce PDT by generating reactive oxygen species (ROS). The ability of X‐rays to penetrate deeply into tissue and efficient ROS diffusion through ultrathin 2D MOLs (ca. 1.2 nm) enable highly effective X‐PDT to afford superb anticancer efficacy.     

Copper(II)–Graphitic Carbon Nitride Triggered Synergy: Improved ROS Generation and Reduced Glutathione Levels for Enhanced Photodynamic Therapy

Graphitic carbon nitride (g‐C₃N₄) has been used as photosensitizer to generate reactive oxygen species (ROS) for photodynamic therapy (PDT). However, its therapeutic efficiency was far from satisfactory. One of the major obstacles was the overexpression of glutathione (GSH) in cancer cells, which could diminish the amount of generated ROS before their arrival at the target site. Herein, we report that the integration of Cu²⁺ and g‐C₃N₄ nanosheets (Cu²⁺–g‐C₃N₄) led to enhanced light‐triggered ROS generation as well as the depletion of intracellular GSH levels. Consequently, the ROS generated under light irradiation could be consumed less by reduced GSH, and efficiency was improved. Importantly, redox‐active species Cu⁺–g‐C₃N₄ could catalyze the reduction of molecular oxygen to the superoxide anion or hydrogen peroxide to the hydroxyl radical, both of which facilitated the generation of ROS. This synergy of improved ROS generation and GSH depletion could enhance the efficiency of PDT for cancer therapy.     

Hybrid TiO2–Ruthenium Nano‐photosensitizer Synergistically Produces Reactive Oxygen Species in both Hypoxic and Normoxic Conditions

Photodynamic therapy (PDT) is widely used to treat diverse diseases, but its dependence on oxygen to produce cytotoxic reactive oxygen species (ROS) diminishes the therapeutic effect in a hypoxic environment, such as solid tumors. Herein, we developed a ROS‐producing hybrid nanoparticle‐based photosensitizer capable of maintaining high levels of ROS under both normoxic and hypoxic conditions. Conjugation of a ruthenium complex (N3) to a TiO₂ nanoparticle afforded TiO₂‐N3. Upon exposure of TiO₂‐N3 to light, the N3 injected electrons into TiO₂ to produce three‐ and four‐fold more hydroxyl radicals and hydrogen peroxide, respectively, than TiO₂ at 160 mmHg. TiO₂‐N3 maintained three‐fold higher hydroxyl radicals than TiO₂ under hypoxic conditions via N3‐facilitated electron–hole reduction of adsorbed water molecules. The incorporation of N3 transformed TiO₂ from a dual type I and II PDT agent to a predominantly type I photosensitizer, irrespective of the oxygen content.     

A mini review of nanomaterials on photodynamic therapy

In this account, the reactive oxygen species (ROS) in photodynamic therapy (PDT) were deliberately reviewed. First, the specific definition of ROS and PDT were readily clarified. Afterward, this review focuses on the fundamental principles and applications of PDT. Due to strong oxidation ability of radicals (e.g., •OH and O₂^•-) and non-radical (e.g., ¹O₂ and H₂O₂), these ROS would attack the in vitro and in vivo tumor cells, thus achieving the goal of cancer treatment. Then, ROS in PDT for cancer treatment was thoroughly reviewed, including the mechanism and photosensitizer (PS) selection (i.e., nanomaterials). Ultimately, emphasis was made on the challenges, research gap, and prospects of ROS in cancer treatment and critically discussed. Hopefully, this review can offer detailed theoretical guidance for the researchers who participate in the study regarding ROS in PDT.     

Tumor microenvironment triggered local oxygen generation and photosensitizer release from manganese dioxide mineralized albumin-ICG nanocomplex to amplify photodynamic immunotherapy efficacy

Photodynamic therapy (PDT) has emerged as a potential clinical strategy for tumor therapy. It can generate reactive oxygen species (ROS) to cause the chemical damage of tumor cells and promote the immune killing effects of T cells on tumor cells in the presence of enough oxygen and PDT drugs. However, most solid tumors are in a state of oxygen deficiency, which seriously limit the efficacy of PDT in generation enough ROS. Besides, few safe PDT drugs with ideal pharmacokinetic behavior are available in the clinic, which severely limits the clinical transformation and application of PDT. Herein, we utilized manganese chloride to mineralize the hydrophilic indocyanine green/albumin polyplexes (ICG@BSA@MnO₂) by using bio-mineralized method to solve these problems of PDT. These ICG@BSA@MnO₂ nanoparticles could circulate in the blood for a long period other than quickly removed from body after 30 min like free ICG. When accumulated at the tumor site, ICG was responsively released in the presence of hydrogen peroxide. Apart this, the tumor hypoxia microenvironment was also reversed owing to enhanced O₂ generation by the reaction of MnO₂ with hydrogen peroxide. Benefits from the rich accumulation of ICG and ameliorated tumor hypoxia in the tumor sites, the enhanced generation of ROS could successfully promote the distribution of CD3⁺ and CD8⁺ T cells inside the tumors, which then lead to the amplified efficacy of PDT in both CT26 and B16F10 tumor models without causing any side effects.     

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.     

Marriage of Scintillator and Semiconductor for Synchronous Radiotherapy and Deep Photodynamic Therapy with Diminished Oxygen Dependence

Strong oxygen dependence and limited penetration depth are the two major challenges facing the clinical application of photodynamic therapy (PDT). In contrast, ionizing radiation is too penetrative and often leads to inefficient radiotherapy (RT) in the clinic because of the lack of effective energy accumulation in the tumor region. Inspired by the complementary advantages of PDT and RT, we present herein the integration of a scintillator and a semiconductor as an ionizing‐radiation‐induced PDT agent, achieving synchronous radiotherapy and depth‐insensitive PDT with diminished oxygen dependence. In the core–shell Ce^III‐doped LiYF₄@SiO₂@ZnO structure, the downconverted ultraviolet fluorescence from the Ce^III‐doped LiYF₄ nanoscintillator under ionizing irradiation enables the generation of electron–hole (e^?–h⁺) pairs in ZnO nanoparticles, giving rise to the formation of biotoxic hydroxyl radicals. This process is analogous to a type I PDT process for enhanced antitumor therapeutic efficacy.     

Deciphering Oxygen-Independent Augmented Photodynamic Oncotherapy by Facilitating the Separation of Electron-Hole Pairs

Developing Type-I photosensitizers provides an attractive approach to solve the dilemma of inadequate efficacy of photodynamic therapy (PDT) caused by the inherent oxygen consumption of traditional Type-II PDT and anoxic tumor microenvironment. The challenge for the exploration of Type-I PSs is to facilitate the electron transfer ability of photosensitization molecules for transforming oxygen or H₂O to reactive oxygen species (ROS). Herein, we propose an electronic acceptor-triggered photoinduced electron transfer (a-PET) strategy promoting the separation of electron-hole pairs by marriage of two organic semiconducting molecules of a non-fullerene scaffold-based photosensitizer and a perylene diimide that significantly boost the Type-I PDT pathway to produce plentiful ROS, especially, inducing 3.5-fold and 2.5-fold amplification of hydroxyl (OH⋅) and superoxide (O₂⁻⋅) generation. Systematic mechanism exploration reveals that intermolecular electron transfer and intramolecular charge separation after photoirradiation generate a competent production of radical ion pairs that promote the Type-I PDT process by theoretical calculation and ultrafast femtosecond transient absorption (fs-TA) spectroscopy. By complementary tumor diagnosis with photoacoustic imaging and second near-infrared fluorescence imaging, this as-prepared nanoplatform exhibits fabulous photocytotoxicity in harsh hypoxic conditions and terrific cancer revoked abilities in living mice. We envision that this work will broaden the insight into high-efficiency Type-I PDT for cancer phototheranostics.     

An azo dye for photodynamic therapy that is activated selectively by two-photon excitation

Two-photon photodynamic therapy (TP-PDT) is a promising approach for the treatment of cancer because of its better penetration depth and superior spatial selectivity. Here, we describe an azo group containing cyclized-cyanine derivatives (ACC1 and ACC2) as a two-photon activated, type I based photosensitizer (PS). These small-molecule and heavy atom-free organic dyes showed marked reactive oxygen species (ROS)-generating ability under physiological conditions, as well as fast loading ability into the cells and negligible dark toxicity. Live cell analyses with one- and two-photon microscopy revealed that these dyes showed higher ROS generation ability upon two-photon excitation than upon one-photon excitation via the type I process. The PSs have superior PDT properties compared to conventional Visudyne and 5-ALA under mild conditions. These characteristics allowed for precise PDT at the target region in mimic tumor spheroids, demonstrating that the developed TP PS could be useful in efficient PDT applications and in designing various PSs.

Azo containing dyes as a two-photon selective and type I based photosensitizers (PSs) were developed that exhibit excellent photodynamic therapy properties under mild condition.     

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.     

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.     

Initiator‐Loaded Gold Nanocages as a Light‐Induced Free‐Radical Generator for Cancer Therapy

Tumor hypoxia greatly suppresses the therapeutic efficacy of photodynamic therapy (PDT), mainly because the generation of toxic reactive oxygen species (ROS) in PDT is highly oxygen‐dependent. In contrast to ROS, the generation of oxygen‐irrelevant free radicals is oxygen‐independent. A new therapeutic strategy based on the light‐induced generation of free radicals for cancer therapy is reported. Initiator‐loaded gold nanocages (AuNCs) as the free‐radical generator were synthesized. Under near‐infrared light (NIR) irradiation, the plasmonic heating effect of AuNCs can induce the decomposition of the initiator to generate alkyl radicals (R^.), which can elevate oxidative‐stress (OS) and cause DNA damages in cancer cells, and finally lead to apoptotic cell death under different oxygen tensions. As a proof of concept, this research opens up a new field to use various free radicals for cancer therapy.     

Antitumor Effect of Sinoporphyrin Sodium‐Mediated Photodynamic Therapy on Human Esophageal Cancer Eca‐109 Cells

The aim of this study was to evaluate the photodynamic effect of Sinoporphyrin sodium (DVDMS). In this study, Eca‐109 cells were treated with DVDMS (5 μg mL^?1) and subjected to photodynamic therapy (PDT). The uptake and subcellular localization of DVDMS were monitored by flow cytometry and confocal microscopy. The phototoxicity of DVDMS was studied by MTT assay. The morphological changes were observed by scanning electron microscopy (SEM). DNA damage, reactive oxygen species (ROS) generation and mitochondria membrane potential (MMP) changes were analyzed by flow cytometry. Studies demonstrated maximal uptake of DVDMS occurred within 3 h, with a mitochondrial subcellular localization. MTT assays displayed that DVDMS could be effectively activated by light and the phototoxicity was much higher than photofrin under the same conditions. In addition, SEM observation indicated that cells were seriously damaged after PDT treatment. Furthermore, activation of DVDMS resulted in significant increases in ROS production. The generated ROS played an important role in the phototoxicity of DVDMS. DVDMS‐mediated PDT (DVDMS‐PDT) also induced DNA damage and MMP loss. It is demonstrated that DVDMS‐mediated PDT is an effective approach on cell proliferation inhibition of Eca‐109 cells.     

Synergistic Anticancer Therapy by Ovalbumin Encapsulation-Enabled Tandem Reactive Oxygen Species Generation

The anticancer efficacy of photodynamic therapy (PDT) is limited due to the hypoxic features of solid tumors. We report synergistic PDT/chemotherapy with integrated tandem Fenton reactions mediated by ovalbumin encapsulation for improved in vivo anticancer therapy via an enhanced reactive oxygen species (ROS) generation mechanism. O₂^.− produced by the PDT is converted to H₂O₂ by superoxide dismutase, followed by the transformation of H₂O₂ to the highly toxic ^.OH via Fenton reactions by Fe²⁺ originating from the dissolution of co-loaded Fe₃O₄ nanoparticles. The PDT process further facilitates the endosomal/lysosomal escape of the active agents and enhances their intracellular delivery to the nucleus—even for drug-resistant cells. Cisplatin generates O₂^.− in the presence of nicotinamide adenine dinucleotide phosphate oxidase and thereby improves the treatment efficiency by serving as an additional O₂^.− source for production of ^.OH radicals. Improved anticancer efficiency is achieved under both hypoxic and normoxic conditions.     

Activatable Type I Photosensitizer with Quenched Photosensitization Pre and Post Photodynamic Therapy

The phototoxicity of photosensitizers (PSs) pre and post photodynamic therapy (PDT), and the hypoxic tumor microenvironment are two major problems limiting the application of PDT. While activatable PSs can successfully address the PS phototoxicity pre PDT, and type I PS can generate reactive oxygen species (ROS) effectively in hypoxic environment, very limited approaches are available for addressing the phototoxicity post PDT. There is virtually no solution available to address all these issues using a single design. Herein, we propose a proof-of-concept on-demand switchable photosensitizer with quenched photosensitization pre and post PDT, which could be activated only in tumor hypoxic environment. Particularly, a hypoxia-normoxia cycling responsive type I PS TPFN-AzoCF₃ was designed to demonstrate the concept, which was further formulated into TPFN-AzoCF₃ nanoparticles (NPs) using DSPE-PEG-2000 as the encapsulation matrix. The NPs could be activated only in hypoxic tumors to generate type I ROS during PDT treatment, but remain non-toxic in normal tissues, pre or after PDT, thus minimizing side effects and improving the therapeutic effect. With promising results in in vitro and in vivo tumor treatment, this presented strategy will pave the way for the design of more on-demand switchable photosensitizers with minimized side effects in the future.     

Synthesis of a Ruthenium(II) Compound based on 5‐(2‐Pyrimidyl)‐1H‐tetrazole for Photodynamic Therapy

Ru^II compounds have been universally investigated due to their unique physical and chemical properties. In this paper, a new Ru^II compound based on 2,2′‐bipy and Hpmtz [2,2′‐bipy = 2,2′‐bipyridine, Hpmtz = 5‐(2‐pyrimidyl)‐1H‐tetrazole], namely [Ru(2,2′‐bipy)₂(pmtz)][PF₆] · 0.5H₂O was prepared and characterized by elemental analysis, IR and single‐crystal X‐ray diffraction. [Ru(2,2′‐bipy)₂(pmtz)][PF₆] · 0.5H₂O shows a mononuclear structure and forms a three‐dimensional network by non‐classic hydrogen bonds. The ability of generation of ROS (reactive oxygen species) makes it has a low phototoxicity IC₅₀ (half‐maximal inhibitory concentration) after Xenon lamp irradiation on Hela cells in vitro. The results demonstrate that [Ru(2,2′‐bipy)₂(pmtz)][PF₆] · 0.5H₂O with high light toxicity and low dark toxicity may be a potential candidate for photodynamic therapy.     

Type I Photosensitizer Targeting G-Quadruplex RNA Elicits Augmented Immunity for Cancer Ablation

Type I photodynamic therapy (PDT) represents a promising treatment modality for tumors with intrinsic hypoxia. However, type I photosensitizers (PSs), especially ones with near infrared (NIR) absorption, are limited and their efficacy needs improvement via new targeting tactics. We develop a NIR type I PS by engineering acridinium derived donor-π-acceptor systems. The PS exhibits an exclusive type I PDT mechanism due to effective intersystem crossing and disfavored energy transfer to O₂, and shows selective binding to G-quadruplexes (G4s) via hydrogen bonds identified by a molecular docking study. Moreover, it enables fluorogenic detection of G4s and efficient O₂⋅⁻ production in hypoxic conditions, leading to immunogenic cell death and substantial variations of gene expression in RNA sequencing. Our strategy demonstrates augmented antitumor immunity for effective ablation of immunogenic cold tumor, highlighting its potential of RNA-targeted type I PDT in precision cancer therapy.     

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.     

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.