Supramolecular agents for combination of photodynamic therapy and other treatments

Photodynamic therapy (PDT) is a promising treatment for cancers such as superficial skin cancers, esophageal cancer, and cervical cancer. Unfortunately, PDT often does not have sufficient therapeutic benefits due to its intrinsic oxygen dependence and the limited permeability of irradiating light. Side effects from “always on” photosensitizers (PSs) can be problematic, and PDT cannot treat tumor metastases or recurrences. In recent years, supramolecular approaches using non-covalent interactions have attracted attention due to their potential in PS development. A supramolecular PS assembly could be built to maximize photodynamic effects and minimize side effects. A combination of two or more therapies can effectively address shortcomings while maximizing the benefits of each treatment regimen. Using the supramolecular assembly, it is possible to design a multifunctional supramolecular PS to exert synergistic effects by combining PDT with other treatment methods. This review provides a summary of important research progress on supramolecular systems that can be used to combine PDT with photothermal therapy, chemotherapy, and immunotherapy to compensate for the shortcomings of PDT, and it provides an overview of the prospects for future cancer treatment advances and clinical applications.

This review provides a summary of important research progress on supramolecular systems that can be used to combine photodynamic therapy (PDT) with photothermal therapy, chemotherapy, and immunotherapy to compensate for the shortcomings of PDT.     

Enhancing the ROS generation ability of a rhodamine-decorated iridium(iii) complex by ligand regulation for endoplasmic reticulum-targeted photodynamic therapy

The endoplasmic reticulum (ER) is a very important organelle responsible for crucial biosynthetic, sensing, and signalling functions in eukaryotic cells. In this work, we established a strategy of ligand regulation to enhance the singlet oxygen generation capacity and subcellular organelle localization ability of a rhodamine-decorated iridium(iii) complex by variation of the cyclometallating ligand. The resulting metal complex showed outstanding reactive oxygen species generation efficiency (1.6-fold higher than that of rose bengal in CH₃CN) and highly specific ER localization ability, which demonstrated the promise of the metal-based photo-theranostic agent by simultaneously tuning the photochemical/physical and biological properties. Additionally, low dark cytotoxicity, high photostability and selective tumour cell uptake were featured by this complex to demonstrate it as a promising candidate in photodynamic therapy (PDT) applications. In vivo near infrared fluorescence (NIRF) imaging and tumour PDT were investigated and showed preferential accumulation at the tumour site and remarkable tumour growth suppression, respectively.

A design strategy for boosting the ROS generation of rhodamine-decorated cyclometallated iridium(iii) complexes by ligand regulation for endoplasmic reticulum-targeted precise photodynamic therapy.     

In vivo therapeutic response monitoring by a self-reporting upconverting covalent organic framework nanoplatform

The real-time and in situ monitoring of reactive oxygen species (ROS) generation is critical for minimizing the nonspecific damage derived from the high doses of ROS required during the photodynamic therapy (PDT) process. However, phototherapeutic agents that can generate ROS-related imaging signals during PDT are rare, hampering the facile prediction of the future therapeutic outcome. Herein, we develop an upconverting covalent organic framework (COF) nanoplatform via a core-mediated strategy and further functionalized it with a singlet oxygen reporter for the efficient near-infrared activated and in situ self-reporting of PDT. In this work, the COF photodynamic efficacy is greatly improved (12.5 times that of irregular COFs) via tailoring the size. Furthermore, this nanoplatform is able to not only produce singlet oxygen for PDT, but it can also emit singlet oxygen-correlated luminescence, allowing the real-time and in situ monitoring of the therapeutic process for cancer cells or solid tumors in vivo via near-infrared luminescence imaging. Thus, our core-mediated synthetic and size-tailored strategy endows the upconverting COF nanoplatform with promising abilities for high-efficacy, deep-tissue, precise photodynamic treatment.

An upconverting covalent organic framework nanoplatform is designed for the first time for the near-infrared activated in situ self-reporting of photodynamic therapy in vivo.     

Phthalocyanine‐Assembled Nanodots as Photosensitizers for Highly Efficient Type I Photoreactions in Photodynamic Therapy

Owing to their unique, nanoscale related optical properties, nanostructures assembled from molecular photosensitizers (PSs) have interesting applications in phototheranostics. However, most nanostructured PS assemblies are super‐quenched, thus, preventing their use in photodynamic therapy (PDT). Although some of these materials undergo stimuli‐responsive disassembly, which leads to partial recovery of PDT activity, their therapeutic potentials are unsatisfactory owing to a limited ability to promote generation reactive oxygen species (ROS), especially via type I photoreactions (i.e., not by ¹O₂ generation). Herein we demonstrate that a new, nanostructured phthalocyanine assembly, NanoPcA, has the ability to promote highly efficient ROS generation via the type I mechanism. The results of antibacterial studies demonstrate that NanoPcA has potential PDT applications.     

Recent advances of AIE light-up probes for photodynamic therapy

As a new non-invasive treatment method, photodynamic therapy (PDT) has attracted great attention in biomedical applications. The advantages of possessing fluorescence for photosensitizers have made it possible to combine imaging and diagnosis together with PDT. The unique features of aggregation-induced emission (AIE) fluorogens provide new opportunities for facile design of light-up probes with high signal-to-noise ratios and improved theranostic accuracy and efficacy for image-guided PDT. In this review, we summarize the recent advances of AIE light-up probes for PDT. The strategies and principles to design AIE photosensitizers and light-up probes are firstly introduced. The application of AIE light-up probes in photodynamic antitumor and antibacterial applications is further elaborated in detail, from binding/targeting-mediated, reaction-mediated, and external stimuli-mediated light-up aspects. The challenges and future perspectives of AIE light-up probes in the PDT field are also presented with the hope to encourage more promising developments of AIE materials for phototheranostic applications and translational research.

AIE fluorogens provide new opportunities for the development of light-up probes for photodynamic therapy.     

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.     

Regulation of redox balance using a biocompatible nanoplatform enhances phototherapy efficacy and suppresses tumor metastasis

Many cancer treatments including photodynamic therapy (PDT) utilize reactive oxygen species (ROS) to kill tumor cells. However, elevated antioxidant defense systems in cancer cells result in resistance to the therapy involving ROS. Here we describe a highly effective phototherapy through regulation of redox homeostasis with a biocompatible and versatile nanotherapeutic to inhibit tumor growth and metastasis. We systematically explore and exploit methylene blue adsorbed polydopamine nanoparticles as a targeted and precise nanocarrier, oxidative stress amplifier, photodynamic/photothermal agent, and multimodal probe for fluorescence, photothermal and photoacoustic imaging to enhance anti-tumor efficacy. Remarkably, following the glutathione-stimulated photosensitizer release to generate exogenous ROS, polydopamine eliminates the endogenous ROS scavenging system through depleting the primary antioxidant, thus amplifying the phototherapy and effectively suppressing tumor growth in vitro and in vivo. Furthermore, this approach enables a robust inhibition against breast cancer metastasis, as oxidative stress is a vital impediment to distant metastasis in tumor cells. Innovative, safe and effective nanotherapeutics via regulation of redox balance may provide a clinically relevant approach for cancer treatment.

Amplified oxidative stress achieved by modulating redox homeostasis with PDA–MB for highly effective synergistic phototherapy to inhibit primary tumors and metastases.     

Near-infrared absorbing Ru(ii) complexes act as immunoprotective photodynamic therapy (PDT) agents against aggressive melanoma

Mounting evidence over the past 20 years suggests that photodynamic therapy (PDT), an anticancer modality known mostly as a local treatment, has the capacity to invoke a systemic antitumor immune response, leading to protection against tumor recurrence. For aggressive cancers such as melanoma, where chemotherapy and radiotherapy are ineffective, immunomodulating PDT as an adjuvant to surgery is of interest. Towards the development of specialized photosensitizers (PSs) for treating pigmented melanomas, nine new near-infrared (NIR) absorbing PSs based on a Ru(ii) tris-heteroleptic scaffold [Ru(NNN)(NN)(L)]Cl_n, were explored. Compounds 2, 6, and 9 exhibited high potency toward melanoma cells, with visible EC₅₀ values as low as 0.292–0.602 μM and PIs as high as 156–360. Single-micromolar phototoxicity was obtained with NIR-light (733 nm) with PIs up to 71. The common feature of these lead NIR PSs was an accessible low-energy triplet intraligand (³IL) excited state for high singlet oxygen (¹O₂) quantum yields (69–93%), which was only possible when the photosensitizing ³IL states were lower in energy than the lowest triplet metal-to-ligand charge transfer (³MLCT) excited states that typically govern Ru(ii) polypyridyl photophysics. PDT treatment with 2 elicited a pro-inflammatory response alongside immunogenic cell death in mouse B16F10 melanoma cells and proved safe for in vivo administration (maximum tolerated dose = 50 mg kg⁻¹). Female and male mice vaccinated with B16F10 cells that were PDT-treated with 2 and challenged with live B16F10 cells exhibited 80 and 55% protection from tumor growth, respectively, leading to significantly improved survival and excellent hazard ratios of ≤0.2.

Ru(ii) photosensitizers (PSs) destroy aggressive melanoma cells, triggering an immune response that leads to protection against tumor challenge and mouse survival.     

Type I photosensitizers based on phosphindole oxide for photodynamic therapy: apoptosis and autophagy induced by endoplasmic reticulum stress

Photodynamic therapy (PDT) is considered a pioneering and effective modality for cancer treatment, but it is still facing challenges of hypoxic tumors. Recently, Type I PDT, as an effective strategy to address this issue, has drawn considerable attention. Few reports are available on the capability for Type I reactive oxygen species (ROS) generation of purely organic photosensitizers (PSs). Herein, we report two new Type I PSs, α-TPA-PIO and β-TPA-PIO, from phosphindole oxide-based isomers with efficient Type I ROS generation abilities. A detailed study on photophysical and photochemical mechanisms is conducted to shed light on the molecular design of PSs based on the Type I mechanism. The in vitro results demonstrate that these two PSs can selectively accumulate in a neutral lipid region, particularly in the endoplasmic reticulum (ER), of cells and efficiently induce ER-stress mediated apoptosis and autophagy in PDT. In vivo models indicate that β-TPA-PIO successfully achieves remarkable tumor ablation. The ROS-based ER stress triggered by β-TPA-PIO-mediated PDT has high potential as a precursor of the immunostimulatory effect for immunotherapy. This work presents a comprehensive protocol for Type I-based purely organic PSs and highlights the significance of considering the working mechanism in the design of PSs for the optimization of cancer treatment protocols.

Phosphindole oxide-based photosensitizers with Type I reactive oxygen species generation ability are developed and used for endoplasmic reticulum stress-mediated photodynamic therapy of tumors.     

Enhancing the photodynamic therapy efficacy of black phosphorus nanosheets by covalently grafting fullerene C60

Few-layer black phosphorus (BP) nanosheets show potential application in biomedicine such as photodynamic therapy (PDT), and are therefore commonly used in anticancer therapy and nanomedicine due to being relatively less invasive. However, they suffer from low ambient stability and poor therapeutic efficacy. Herein, C₆₀ was covalently grafted onto the edges of BP nanosheets, and the resultant BP-C₆₀ hybrid was applied as a novel endocytosing photosensitizer, resulting in not only significantly enhanced PDT efficacy relative to that of the pristine BP nanosheets, but also drastically improved stability in a physiological environment, as confirmed by both in vitro and in vivo studies. Such improved stability was due to shielding effect of the stable hydrophobic C₆₀ molecules. The enhanced PDT efficacy is interpreted from the photoinduced electron transfer from BP to C₆₀, leading to the promoted generation of ˙OH radicals, acting as a reactive oxygen species (ROS) that is effective in killing tumor cells. Furthermore, the BP-C₆₀ hybrid exhibited low systemic toxicity in the major organs of mice. The BP-C₆₀ hybrid represents the first BP-fullerene hybrid nanomaterial fulfilling promoted ROS generation and consequently enhanced PDT efficacy.

Covalently grafting C₆₀ molecules onto black phosphorus (BP) nanosheets improves their tumor inhibition rate from 36.6% to 88.2%.     

Designing a highly stable coordination-driven metallacycle for imaging-guided photodynamic cancer theranostics

Coordination-driven self-assembly features good predictability and directionality in the construction of discrete metallacycles and metallacages with well-defined sizes and shapes, but their medicinal application has been limited by their low stability and solubility. Herein, we have designed and synthesized a highly stable coordination-driven metallacycle with desired functionality derived from a perylene-diimide ligand via a spontaneous deprotonation self-assembly process. Brilliant chemical stability and singlet oxygen production ability of this emissive octanuclear organopalladium macrocycle make it a good candidate toward biological studies. After cellular uptake by endocytosis, the metallacycle exhibits potent fluorescence cell imaging properties and cancer photodynamic therapeutic ability through enhancing ROS production, with high biocompatibility and safety. This study not only provides a rational design strategy for highly stable luminescent organopalladium metallacycles, but also sheds light on their application in imaging-guided photodynamic cancer therapy.

A highly-luminescent metallacycle with chemical stability and singlet oxygen production ability were obtained by a spontaneous deprotonation self-assembly process, which exhibits application potential in imaging-guided photodynamic cancer therapy.     

A pH reversibly activatable NIR photothermal/photodynamic-in-one agent integrated with renewable nanoimplants for image-guided precision phototherapy

Phototherapy has great potential to revolutionize conventional therapeutic modalities. However, most phototherapeutic strategies based on multicomponent therapeutic agents generally lack tumor-specificity, resulting in asynchronous therapy and superimposed side-effects. Severe heat damage is also inevitable because of the necessity of continuous external irradiation. Here we show the design of an acid-activated and continuous external irradiation-free photothermal and photodynamic (PTT/PDT) synchronous theranostic nanoplatform for precision tumor-targeting near-infrared (NIR) image-guided therapy. pH-reversibly responsive brominated asymmetric cyanine is designed as the tumor-specific NIR PTT/PDT-in-one agent to enhance anticancer efficiency and reduce side-effects. Ultra-small NIR persistent luminescence nanoparticles are prepared as both the imaging unit and renewable nanoimplant. Biotin functionalized polyethylene glycol is introduced to endow active tumor-targeting ability and prolong blood-circulation. The developed smart platform offers merits of reversible activation, PTT/PDT synergetic enhancement, tumor targetability and continuous external irradiation-free properties, allowing autofluorescence-free image-guided phototherapy only in tumor sites. This work paves the way to developing smart theranostic nanoplatforms for precision medicine.

A smart NIR photothermal/photodynamic-in-one agent integrated with renewable nanoimplants for autofluorescence- and continuous external irradiation-free image-guided precision tumor-targeting phototherapy.     

Cyclooctatetraene-conjugated cyanine mitochondrial probes minimize phototoxicity in fluorescence and nanoscopic imaging

Modern fluorescence-imaging methods promise to unveil organelle dynamics in live cells. Phototoxicity, however, has become a prevailing issue when boosted illumination applies. Mitochondria are representative organelles whose research heavily relies on optical imaging, yet these membranous hubs of bioenergy are exceptionally vulnerable to photodamage. We report that cyclooctatetraene-conjugated cyanine dyes (PK Mito dyes), are ideal mitochondrial probes with remarkably low photodynamic damage for general use in fluorescence cytometry. In contrast, the nitrobenzene conjugate of Cy3 exhibits enhanced photostability but unaffected phototoxicity compared to parental Cy3. PK Mito Red, in conjunction with Hessian-structural illumination microscopy, enables 2000-frame time-lapse imaging with clearly resolvable crista structures, revealing rich mitochondrial dynamics. In a rigorous stem cell sorting and transplantation assay, PK Mito Red maximally retains the stemness of planarian neoblasts, exhibiting excellent multifaceted biocompatibility. Resonating with the ongoing theme of reducing photodamage using optical approaches, this work advocates the evaluation and minimization of phototoxicity when developing imaging probes.

Cyclooctatetraene-conjugated cyanine dyes represent an effective strategy to improve biocompatibility under light in live-cell fluorescence imaging and analysis of mitochondria.     

Rational design of a “dual lock-and-key” supramolecular photosensitizer based on aromatic nucleophilic substitution for specific and enhanced photodynamic therapy

Photosensitizing agents are essential for precise and efficient photodynamic therapy (PDT). However, most of the conventional photosensitizers still suffer from limitations such as aggregation-caused quenching (ACQ) in physiological environments and toxic side-effects on normal tissues during treatment, leading to reduced therapeutic efficacy. Thus, integrating excellent photophysical properties and accurate carcinoma selectivity in a photosensitizer system remains highly desired. Herein, a “dual lock-and-key” supramolecular photosensitizer BIBCl–PAE NPs for specific and enhanced cancer therapy is reported. BIBCl–PAE NPs are constructed by encapsulating a rationally designed glutathione (GSH)-activatable photosensitizer BIBCl in a pH-responsive diblock copolymer. In normal tissues, BIBCl is “locked” in the hydrophobic core of the polymeric micelles due to ACQ. Under the “dual key” activation of low pH and high levels of GSH in a tumor microenvironment, the disassembly of micelles facilitates the reaction of BIBCl with GSH to release water-soluble BIBSG with ideal biocompatibility, enabling the highly efficient PDT. Moreover, benefiting from the Förster resonance energy transfer effect of BIBSG, improved light harvesting ability and ¹O₂ production are achieved. In vitro and vivo experiments have demonstrated that BIBCl–PAE NPs are effective in targeting and inhibiting carcinoma. BIBCl–PAE NPs show superior anticancer efficiency relative to non-activatable controls.

The “dual lock-and-key” supramolecular photosensitizers enable specific and enhanced photodynamic therapy (PDT).     

Design of BODIPY dyes as triplet photosensitizers: electronic properties tailored for solar energy conversion,photoredox catalysis and photodynamic therapy

BODIPYs are renowned fluorescent dyes with strong and tunable absorption in the visible region, high thermal and photo-stability and exceptional fluorescence quantum yields. Transition metal complexes are the most commonly used triplet photosensitisers, but, recently, the use of organic dyes has emerged as a viable and more sustainable alternative. By proper design, BODIPY dyes have been turned from highly fluorescent labels into efficient triplet photosensitizers with strong absorption in the visible region (from green to orange). In this perspective, we report three design strategies: (i) halogenation of the dye skeleton, (ii) donor–acceptor dyads and (iii) BODIPY dimers. We compare pros and cons of these approaches in terms of optical and electrochemical properties and synthetic viability. The potential applications of these systems span from energy conversion to medicine and key examples are presented.

BODIPYs offer a versatile platform to build organic triplet photosensitisers for PDT, TTA upconversion and photocatalysis. Tuning their properties provides the opportunity of replacing heavy-metal complexes and can lead to improved sustainability.     

Type I macrophage activator photosensitizer against hypoxic tumors

Photodynamic immunotherapy has emerged as a promising strategy to treat cancer. However, the hypoxic nature of most solid tumors and notoriously immunosuppressive tumor microenvironment could greatly compromise the efficacy of photodynamic immunotherapy. To address this challenge, we rationally synthesized a type I photosensitizer of TPA-DCR nanoparticles (NPs) with aggregation-enhanced reactive oxygen species generation via an oxygen-independent pathway. We demonstrated that the free radicals produced by TPA-DCR NPs could reprogram M0 and M2 macrophages into an anti-tumor state, which is not restricted by the hypoxic conditions. The activated M1 macrophages could further induce the immunogenic cell death of cancer cells by secreting pro-inflammatory cytokines and phagocytosis. In addition, in vivo anti-tumor experiments revealed that the TPA-DCR NPs could further trigger tumor immune response by re-educating tumor-associated macrophages toward M1 phenotype and promoting T cell infiltration. Overall, this work demonstrates the design of type I organic photosensitizers and mechanistic investigation of their superior anti-tumor efficacy. The results will benefit the exploration of advanced strategies to regulate the tumor microenvironment for effective photodynamic immunotherapy against hypoxic tumors.

The photosensitizer-triggered macrophage-mediated photodynamic immunotherapy is reported. The TPA-DCR NPs induce the ICD of hypoxic tumor by generating type I ROS to polarize macrophage, then promote tumor infiltration of T cells.     

A photo-sensitizable phage for multidrug-resistant Acinetobacter baumannii therapy and biofilm ablation

Antibiotic abuse causes the emergence of bacterial resistance. Photodynamic antibacterial chemotherapy (PACT) has great potential to solve serious bacterial resistance, but it suffers from the inefficient generation of ROS and the lack of bacterial targeting ability. Herein, a unique cationic photosensitizer (NB) and bacteriophage (ABP)-based photodynamic antimicrobial agent (APNB) is developed for precise bacterial eradication and efficient biofilm ablation. Thanks to the structural modification of the NB photosensitizer with a sulfur atom, it displays excellent reactive oxygen species (ROS)-production ability. Moreover, specific binding to pathogenic microorganisms can be provided by bacteriophages. The developed APNB has multiple functions, including bacteria targeting, near-infrared fluorescence imaging and combination therapy (PACT and phage therapy). Both in vitro and in vivo experiments prove that APNB can efficiently treat A. baumannii infection. Particularly, the recovery from A. baumannii infection after APNB treatment is faster than that with ampicillin and polymyxin B in vivo. Furthermore, the strategy of combining bacteriophages and photosensitizers is employed to eradicate bacterial biofilms for the first time, and it shows the excellent biofilm ablation effect as expected. Thus, APNB has huge potential in fighting against multidrug-resistant bacteria and biofilm ablation in practice.

APNB for multidrug-resistant A. Baumannii therapy and biofilms ablation.     

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.     

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.     

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.