Phototherapy Agents Research Articles

Thienothiophene-Benzopyran Derivative and AQ4N-Assembled Liposomes for Near-Infrared II Fluorescence Imaging-Guided Phototherapy, Chemotherapy, and Immune Activation.

Phototherapy, including photodynamic therapy (PDT) and photothermal therapy (PTT), has attracted wide attention in tumor treatment. However, the hypoxic tumor microenvironment and the heat shock proteins produced by tumor cells significantly reduce their efficacy. Developing effective phototherapy agents that have high reactive oxygen species generation efficiency and photothermal conversion efficiency (PCE) while simultaneously utilizing the hypoxic tumor microenvironment is of great importance. Here, a thienothiophene-benzopyran derivative, BTPIC4F-C10 is designed and synthesized, with near-infrared (NIR) absorption and fluorescence. Then the lipid nanoparticles (LipBFCA NPs) which encapsulated BTPIC4F-C10 in a phospholipid bilayer together with hypoxia-activated prodrug banoxanthrone (AQ4N) are constructed for NIR-II fluorescence imaging-guided synergistic PDT/PTT/chemotherapy and immune activation. Under 808nm laser irradiation, LipBFCA NPs is a high singlet oxygen quantum yield of 20.2% and PCE of 78.8%. With ultra-high photon energy utilization efficiency of 99%, LipBFCA NPs is an excellent phototherapy effect. The hypoxic environment caused by phototherapy can further activate AQ4N to transform into chemically toxic AQ4 radicals to kill tumor cells. Moreover, phototherapy can induce immunogenic cell death, release tumor-associated antigens, and activate immune responses. This work provides a new way for the clinical application of fluorescence imaging in guiding tumor diagnosis and treatment.

MOF-Enhanced Phototherapeutic Wound Dressings Against Drug-Resistant Bacteria.

Phototherapy is a low-risk alternative to traditional antibiotics against drug-resistant bacterial infections. However, optimizing phototherapy agents, refining treatment conditions, and addressing misuse of agents, remain a formidable challenge. This study introduces a novel concept leveraging the unique customizability of metal-organic frameworks (MOFs) to house size-matched dye molecules in "single rooms". The mesoporous iron(III) carboxylate nanoMOF, MIL-100(Fe), and the hydrophobic heptamethine cyanine photothermal dye (Cy7), IR775, are selected as model systems. Their combination is predicted to minimize dye-dye interactions, leading to exceptional photostability and efficient light-to-heat conversion. Furthermore, MIL-100(Fe) preserves the antimicrobial nature of hydrophobic IR775, enabling it to disrupt bacterial cell envelopes. Through electrospinning, MIL-100(Fe)@IR775 nanoparticles are shaped into a gelatin-based film dressing for the treatment of skin wounds infected by Methicillin-resistant Staphylococcus aureus (MRSA). Activation of the dressing requires only a portable near-infrared light-emitting diode (NIR LED) and induces both low-dose photodynamic therapy (LPDT) and mild-temperature photothermal therapy (MPTT). Combined with the antimicrobial properties of IR775 and ferroptosis-like lipid peroxidation induced by MIL-100(Fe), the photoactive dressing eradicates MRSA and the healing is as quick as the uninfected wounds. This safe, cost-effective, and multifunctional therapeutic wound dressing offers a promising solution to overcome the current bottleneck in phototherapy.

Enhanced Photodynamic Therapy for Neurodegenerative Diseases: Development of Azobenzene-Spiropyran@Gold Nanoparticles for Controlled Singlet Oxygen Generation.

The development of durable photosensitizers is pivotal for advancing phototherapeutic applications in biomedicine. Here, we introduce a core-shell azobenzene-spiropyran structure on gold nanoparticles, engineered to enhance singlet oxygen generation. These nano-photosensitizers exhibit increased structural stability and thermal resistance, as demonstrated by slowed O-N-C bond recombination dynamics via in-situ Raman spectroscopy. Notably, the in-situ formation of merocyanine and a light-induced compact shell arrangement extend its half-life from 47 minutes to over 154 hours, significantly boosting singlet oxygen output. The nano-photosensitizer also shows high biocompatibility and notably inhibits tau protein aggregation in neural cells, even with phosphatase inhibitors. Further, it promotes dendritic growth in neuro cells, doubling typical lengths. This work not only advances chemical nanotechnology but also sets a foundation for developing long-lasting phototherapy agents for treating neurodegenerative diseases.

Win-win integration: A mitochondria targeted AIE photosensitizer for hypochlorite detection and type I & type II photodynamic therapy

BackgroundPhotodynamic therapy (PDT) is a pioneering and effective anticancer modality with low adverse effects and high selectivity. Hypochlorous acid or hypochlorite (HClO/ClO−) is a type of inflammatory cytokine. The abnormal increase of ClO− in tumor cells is related to tumor pathogenesis and may be a “friend” for the design and synthesis of responsive phototherapy agents. However, preparing responsive phototherapy agents for all-in-one noninvasive diagnosis and simultaneous in situ therapy in a complex tumor environment is highly desirable but still remains an enormously demanding task. ResultsAn acceptor-π bridge-donor-π bridge-acceptor (A-π-D-π-A) type photosensitizer TPTPy was designed and synthesized based on the phenothiazine structure which was used as the donor moiety as well as a ClO− responsive group. TPTPy was a multifunctional mitochondria targeted aggregation-induced emission (AIE) photosensitizer which could quickly and sensitively respond to ClO− with fluorescence “turn on” performance (19-fold fluorescence enhancement) and enhanced type I reactive oxygen species (ROS) generation to effectively ablate hypoxic tumor cells. The detection limit of TPTPy to ClO− was calculated to be 185.38 nM. The well-tailored TPTPy anchoring to mitochondria and producing ROS in situ could disrupt mitochondria and promote cell apoptosis. TPTPy was able to image inflammatory cells and tumor cells through ClO− response. In vivo results revealed that TPTPy was successfully utilized for PDT in tumor bearing nude mice and exhibited excellent biological safety for major organs. Significance and noveltyA win-win integration strategy was proposed to design a tumor intracellular ClO− responsive photosensitizer TPTPy capable of both type I and type II ROS production to achieve photodynamic therapy of tumor. This work sheds light on the win-win integration design by taking full advantage of the characteristics of tumor microenvironment to build up responsive photosensitizer for in situ PDT of tumor.

Magnetic‐Driven Hydrogel Spiral PVA/Fe3O4 Micromotors for Targeted Photothermal Therapy

AbstractPhototherapy has emerged as a promising technique for cancer treatment, offering high efficiency and minimal side effects. Nevertheless, conventional phototherapy agents suffer from low targetability and inefficient delivery. Here, a novel approach is proposed using helical hydrogel motors fabricated by combining polyvinyl alcohol, melamine, water, and Fe3O4 nanoparticles. These magnetic motors are capable of precise therapy on tumor cells driven by an external magnetic field. By converting light into heat upon near‐infrared illumination, the motors elevate the temperature of the targeted region, resulting in a significant therapeutic effect, with over 60% eradication of HeLa cells achieve under 808 nm near‐ infrared light (1.5 W cm−2). These helical micromotors exhibit excellent movement performance and biocompatibility, facilitating their in vivo applications and contributing to the advancement of biomedicine.

Recent Advances in Chemistry, Mechanism, and Applications of Quantum Dots in Photodynamic and Photothermal Therapy.

Semiconductor quantum dots (QD) are a kind of nanoparticle with unique optical properties that have attracted a lot of attention in recent years. In this paper, the characteristics of these nanoparticles and their applications in nanophototherapy have been reviewed. Phototherapy, including photodynamic therapy (PDT) and photothermal therapy (PTT), has gained special importance because of its high accuracy and local treatment due to the activation of the drug at the tumor site. PDT is a new way of cancer treatment that is performed by activating light-sensitive compounds named photosensitizers (PS) by light. PSs cause the destruction of diseased tissue through the production of singlet oxygen. PTT is another non-invasive method that induces cell death through the conversion of near-infrared light (NIR) into heat in the tumor situation by the photothermal agent (PA). Through using energy transfer via the FRET (Förster resonance energy transfer) process, QDs provide light absorption wavelength for both methods and cover the optical weaknesses of phototherapy agents.

Tailored Phototherapy Agent by Infection Site In Situ Activated Against Methicillin-Resistant S. aureus.

Phototherapy, including photodynamic therapy (PDT) and photothermal therapy (PTT), is a promising treatment approach for multidrug resistant infections. PDT/PTT combination therapy can more efficiently eliminate pathogens without drug resistance. The key to improve the efficacy of photochemotherapy is the utilization efficiency of non-radiation energy of phototherapy agents. Herein, a facile phototherapy molecule (SCy-Le) with the enhancement of non-radiative energy transfer is designed by an acid stimulation under a single laser. Introduction of the protonated receptor into SCy-Le results in a distorted intramolecular charge in the infected acidic microenvironment, pH ≈ 5.5, which in turn, enhances light capture, reduces the singlet-triplet transition energies (ΔES1-T1), promotes electron system crossing, enhances capacity of reactive oxygen speciesgeneration, and causes a significant increase in temperature by improving vibrational relaxation. SCy-Le shows more than 99% bacterial killing rate against both methicillin-resistant Staphylococcus aureus and its biofilms in vitro and causes bacteria-induced wound healing in mice. This work will provide a new perspective for the design of phototherapy agents, and the emerging photochemotherapy will be a promising approach to combat the problem of antibiotic resistance.

Multimodal phototherapy agents target lipid droplets for near-infrared imaging-guided type I photodynamic/photothermal therapy

The construction and optimization of a single phototherapeutic agent with photoluminescence, type I photodynamic therapy (PDT), and photothermal therapy (PTT) functions remain challenging. In this study, we aimed to design and synthesize four donor–acceptor (D-A) type aggregation-induced emission molecules: PSI, TPSI, PSSI, and TPSSI. We employed phenothiazine as an electron donor and 1,3-bis(dicyanomethylidene)indan as a strong electron acceptor in the synthesis process. Among them, TPSSI exhibited efficient type I reactive oxygen species generation, high photothermal conversion efficiency (45.44 %), and near-infrared emission. These observations can be attributed to the introduction of a triphenylamine electron donor group and a thiophene unit, which resulted in increased D–A strengths, a reduced singlet-triplet energy gap, and increased free intramolecular motion. TPSSI was loaded into bovine serum albumin to prepare biocompatible TPSSI nanoparticles (NPs). Our results have indicated that TPSSI NPs can target lipid droplets with negligible dark toxicity and can efficiently generate O2•− in hypoxic tumor environments. Moreover, TPSSI NPs selectively targeted 4T1 tumor tissues and exhibited a good PDT-PTT synergistic effect in vitro and in vivo. We believe that the successful preparation of multifunctional phototherapeutic agents will promote the development of efficient tumor diagnosis and treatment technologies. Statement of SignificanceThe construction of a single phototherapeutic agent with photoluminescence, type I photodynamic therapy, and photothermal therapy functions, and its optimization remain challenging. In this study, we construct four donor–acceptor aggregation-induced emission molecules using phenothiazine as an electron donor and 1,3-Bis(dicyanomethylidene)indan as a strong electron acceptor. By optimizing the molecular structure, an integrated phototherapy agent with fluorescence imaging ability and high photodynamic / photothermal therapy performance was prepared. We believe that the successful preparation of multifunctional phototherapeutic agents will promote the development of efficient tumor diagnosis and treatment technology.

Suitable Isolation Side Chains: A Simple Strategy for Simultaneously Improving the Phototherapy Efficacy and Biodegradation Capacities of Conjugated Polymer Nanoparticles.

Utilizing one molecule to realize combinational photodynamic and photothermal therapy upon single-wavelength laser excitation, which relies on a multifunctional phototherapy agent, is one of the most cutting-edge research directions in tumor therapy owing to the high efficacy achieved over a short course of treatment. Herein, a simple strategy of "suitable isolation side chains" is proposed to collectively improve the fluorescence intensity, reactive oxygen species production, photothermal conversion efficiency, and biodegradation capacity. Both in vitro and in vivo results reveal the practical value and huge potential of the designed biodegradable conjugated polymer PTD-C16 with suitable isolation side chains in fluorescence image-guided combinational photodynamic and photothermal therapy. These improvements are achieved through manipulation of aggregated states by only side chain modification without changing any conjugated structure, providing new insight into the design of biodegradable high-performance phototherapy agents.

Multifunctional agents based on 3-dicycanovinylindan-1-one acceptor: Molecular design and phototheranostic application.

Phototherapy, including photodynamic therapy (PDT) and photothermal therapy (PTT), has garnered considerable attention in recent years, owing to its precise spatiotemporal accuracy with minimal side effects. Recent research reveals that the combination of PDT and PTT exhibits a remarkable anti-tumor efficacy compared to PDT or PTT alone, which has put forward the new requirements of multifunctional phototherapy agents with both high photosensitization and photothermal conversion efficiencies. Among the newly developed multifunctional agents, the ones with one or two 3-dicycanovinylindan-1-one (IC) moieties as the acceptors attract much more attention, due to their long-wavelength excitation and emission, as well as high phototherapy efficacies. Therefore, in this review, the latest advancement of multifunctional agents based on IC acceptor is summarized. Especially, we focus on the structure-property relationships of the agents, as well as their biomedical application in anti-tumor therapy or image-guided therapy. Our perspective on the further future development of this field is also discussed to conclude.

Degradable bifunctional phototherapy composites based on upconversion nanoparticle-metal phenolic network for multimodal tumor therapy in the near-infrared biowindow

Phototherapy has garnered increasing attention as it allows for precise treatment of tumor sites with its accurate spatiotemporal control. In this study, we have successfully synthesized degradable bifunctional phototherapy agents (UCNPs@mSiO2@MPN-MC540/DOX) based on upconversion nanoparticle (UCNPs) and metal phenolic network (MPN), serving as a novel nanoplatform for multimodal tumor treatment in the near-infrared (NIR) biological window. To address the issue of low light penetration depth, the UCNPs we synthesized exhibited efficient light conversion ability under 808 nm laser irradiation to activate the photosensitizer Merocyanine 540 (MC540) for photodynamic therapy. Simultaneously, the 808 nm NIR light can also excite the MPN layer to achieve photothermal therapy for tumors. Additionally, the MPN layer possesses the capability of self-degradation under weakly acidic conditions. Within the tumor microenvironment, the MPN layer gradually degrades, facilitating the controlled release of the chemotherapy drug doxorubicin (DOX), thus achieving pH-responsive drug release and reducing the side effects of chemotherapy. This study provides an example of NIR-excited multimodal tumor treatment and pH-responsive drug release, offering a therapy model for precise tumor therapy.

Recent advances in phototherapeutic nanosystems for oral cancer.

Oral cancer is a significant global health challenge, with conventional treatments often resulting in substantial side effects and limited effectiveness. Phototherapy, encompassing photodynamic and photothermal therapy, presents a promising alternative by selectively targeting and destroying cancer cells with minimal systemic toxicity. However, issues such as insufficient light penetration and limited tumor specificity have restricted their clinical use. Recent advancements in nanosystems have addressed these challenges by enhancing the solubility, stability, and tumor-targeting capabilities of phototherapy agents. This review delves into the latest advancements in phototherapeutic nanosystems for oral cancer, focusing on the design of innovative nanoformulations and targeted delivery strategies. Additionally, it summarizes recent approaches to enhance the efficacy of photodynamic therapy for oral cancer and examines phototherapy-based combination treatments. These advancements hold the promise of significantly improving treatment outcomes while minimizing side effects in oral cancer therapy.

Ru(II) Phenanthroline-Based Oligothienyl Complexes as Phototherapy Agents.

Ru(II) polypyridyl complexes have gained widespread attention as photosensitizers for photodynamic therapy (PDT). Herein, we systematically investigate a series of the type [Ru(phen)2(IP-nT)]2+, featuring 1,10-phenanthroline (phen) coligands and imidazo[4,5-f][1,10]phenanthroline ligands tethered to n = 0-4 thiophene rings (IP-nT). The complexes were characterized and investigated for their electrochemical, spectroscopic, and (photo)biological properties. The electrochemical oxidation of the nT unit shifted by -350 mV as n = 1 → 4 (+920 mV for Ru-1T, +570 mV for Ru-4T); nT reductions were observed in complexes Ru-3T (-2530 mV) and Ru-4T (-2300 mV). Singlet oxygen quantum yields ranged from 0.53 to 0.88, with Ru-3T and Ru-4T being equally efficient (∼0.88). Time-resolved absorption spectra of Ru-0T-1T were dominated by metal-to-ligand charge-transfer (3MLCT) states (τTA = 0.40-0.85 μs), but long-lived intraligand charge-transfer (3ILCT) states were observed in Ru-2T-4T (τTA = 25-148 μs). The 3ILCT energies of Ru-3T and Ru-4T were computed to be 1.6 and 1.4 eV, respectively. The phototherapeutic efficacy against melanoma cells (SK-MEL-28) under broad-band visible light (400-700 nm) increases as n = 0 → 4: Ru-0T was inactive up to 300 μM, Ru-1T-2T were moderately active (EC50 ∼ 600 nM, PI = 200), and Ru-3T (EC50 = 57 nM, PI > 1100) and Ru-4T (EC50 = 740 pM, PI = 114,000) were the most phototoxic. The activity diminishes with longer wavelengths of light and is completely suppressed for all complexes except Ru-3T and Ru-4T in hypoxia. Ru-4T is the more potent and robust PS in 1% O2 over seven biological replicates (avg EC50 = 1.3 μM, avg PI = 985). Ru-3T exhibited hypoxic activity in five of seven replicates, underscoring the need for biological replicates in compound evaluation. Singlet oxygen sensitization is likely responsible for phototoxic effects of the compounds in normoxia, but the presence of redox-active excited states may facilitate additional photoactive pathways for complexes with three or more thienyl groups. The 3ILCT state with its extended lifetime (30-40× longer than the 3MLCT state for Ru-3T and Ru-4T) implicates its predominant role in photocytotoxicity.

An injectable and thermosensitive hydrogel with nano-aided NIR-II phototherapeutic and chemical effects for periodontal antibacteria and bone regeneration

Periodontitis is a common public health problem worldwide and an inflammatory disease with irregular defect of alveolar bone caused by periodontal pathogens. Both antibacterial therapy and bone regeneration are of great importance in the treatment of periodontitis. In this study, injectable and thermosensitive hydrogels with 3D networks were used as carriers for controlled release of osteo-inductive agent (BMP-2) and Near Infrared Region-II (NIR-II) phototherapy agents (T8IC nano-particles). T8IC nano-particles were prepared by reprecipitation and acted as photosensitizer under 808 nm laser irradiation. Besides, we promoted photodynamic therapy (PDT) through adding H2O2 to facilitate the antibacterial effect instead of increasing the temperature of photothermal therapy (PTT). Hydrogel + T8IC + Laser + BMP-2 + H2O2 incorporated with mild PTT (45 °C), enhanced PDT and sustained release of BMP-2. It was present with excellent bactericidal effect, osteogenic induction and biosafety both in vitro and in vivo. Besides, immunohistochemistry staining and micro-CT analyses had confirmed that PTT and PDT could promote bone regeneration through alleviating inflammation state. Altogether, this novel approach with synergistic antibacterial effect, anti-inflammation and bone regeneration has a great potential for the treatment of periodontitis in the future.

Polypyrrole hydrogel with near-infrared light-driven nitric oxide release and photothermal activities for rapid synergistic sterilization and infected wound therapy

Developing low-cost and easy-accessible phototherapy agents with a high sterilization efficiency is urgently needed tackling the increasingly dangerous of bacterial infections. Herein, a broad-spectrum antimicrobial agent (i.e., PP-Mo-NO) with near-infrared laser (NIR) driven nitric oxide (NO) release capacity derived from the assemble of a heat-sensitive NO donor (N, N′-di-sec-butyl-N, N′-dinitroso-1, 4-phenylenediamine, BNN6) with freeze-dried three-dimensional polypyrrole hydrogel crosslinked by the sulfonated dimolybdenum-salen (PP-Mo), was synthesized for the rapid and effective eradicating of Gram-negative Escherichia coli (E. coli) and Gram-positive Staphylococcus aureus (S. aureus). Upon 808 nm laser irradiation, PP-Mo-NO showed not only superb photothermal efficacy (79.88 %), but also precisely controllable NO release capacity, generating oxidative/nitrosative stress. Within 10 mins of irradiation (1.0 W cm−2), PP-Mo-NO with co-amplified photothermal (PTT)/NO synergetic antibacterial activity presented sterilization rates beyond 99.1% against both the E. coli and S. aureus at a relatively low concentration (100 µg mL−1). Meanwhile, in vivo experiments demonstrated the great application potential of PP-Mo-NO which could effectively kill bacteria at the site of infection, and repair the open infectious wounds, thereby accelerating the tissue reconstruction.

A dipyridophenazine Ni(II) dithiolene complex as a dual-acting cancer phototherapy agent activatable within the phototherapeutic window

A combination of photodynamic therapy (PDT) and photothermal therapy (PTT) within the phototherapeutic window (600–900 nm) can lead to significantly enhanced therapeutic outcomes, surpassing the efficacy observed with PDT or PTT alone in cancer phototherapy. Herein, we report a novel small-molecule mixed-ligand Ni(II)-dithiolene complex (Ni-TDD) with a dipyridophenazine ligand, demonstrating potent red-light PDT and significant near-infrared (NIR) light mild-temperature PTT activity against cancer cells and 3D multicellular tumour spheroids (MCTSs). The four-coordinate square planar complex exhibited a moderately intense absorption band (ε ∼ 3700 M−1cm−1) centered around 900 nm and demonstrated excellent dark and photostability in an aqueous phase. Ni-TDD induced a potent red-light (600–720 nm) PDT effect on HeLa cancer cells (IC50 = 1.8 μM, photo irritation factor = 44), triggering apoptotic cell death through efficient singlet oxygen generation. Ni-TDD showed a significant intercalative binding affinity towards double-helical calf thymus DNA, resulting in a binding constant (Kb) ∼ 106 M−1. The complex induced mild hyperthermia and exerted a significant mild-temperature PTT effect on MDA-MB-231 cancer cells upon irradiation with 808 nm NIR light. Simultaneous irradiation of Ni-TDD-treated HeLa MCTSs with red and NIR light led to a remarkable synergistic inhibition of growth, exceeding the effects of individual irradiation, through the generation of singlet oxygen and mild hyperthermia. Ni-TDD displayed minimal toxicity towards non-cancerous HPL1D and L929 cells, even at high micromolar concentrations. This is the first report of a Ni(II) complex demonstrating red-light PDT activity and the first example of a first-row transition metal complex exhibiting combined PDT and PTT effects within the clinically relevant phototherapeutic window. Our findings pave the way for designing and developing metal-dithiolene complexes as dual-acting cancer phototherapy agents using long wavelength light for treating solid tumors.

Synthesis of germanium/germanium phosphide in-plane heterostructure with efficient photothermal and enhanced photodynamic effects in the second near-infrared biowindow

Inspired by the bifunctional phototherapy agents (PTAs), constructing compact PTAs with efficient photothermal therapy (PTT) and photodynamic therapy (PDT) effects in the near-infrared (NIR-II) biowindow is crucial for high therapeutic efficacy. Herein, none-layered germanium (Ge) is transformed to layered Ge/germanium phosphide (Ge/GeP) structure, and a novel two-dimensional sheet-like compact S-scheme Ge/GeP in-plane heterostructure with a large extinction coefficient of 15.66 L/g cm−1 at 1,064 nm is designed and demonstrated. In addition to the outstanding photothermal effects, biocompatibility and degradability, type I and type II PDT effects are activated by a single laser. Furthermore, enhanced reactive oxygen species generation under longer wavelength NIR laser irradiation is achieved, and production of singlet oxygen and superoxide radical upon 1,064 nm laser irradiation is more than double that under 660 nm laser irradiation. The S-scheme charge transfer mechanism between Ge and GeP, is demonstrated by photo-irradiated Kelvin probe force microscopy and electron spin resonance analysis. Thus, the obtained S-scheme Ge/GeP in-plane heterostructure shows synergistic therapeutic effects of PTT/PDT both in vitro and in vivo in the NIR-II biowindow and the novel nanoplatform with excellent properties has large clinical potential.

Hydrogen Sulfide Responsive Phototherapy Agents: Design Strategies and Biological Applications.

Hydrogen sulfide (H2S) is one of the critical gasotransmitters, which play important roles in regular physiological processes, especially in vital signaling pathways. However, fluctuations in endogenous H2S concentration can be linked to serious health problems, such as neurodegenerative diseases, cancer, diabetes, inflammation, cardiovascular diseases, and hypertension. Thus, it has attracted a great deal of attention in therapeutic applications, specifically in the field of phototherapy. Photodynamic therapy (PDT) and photothermal therapy (PTT) are two subclasses of phototherapy, which utilize either reactive oxygen species (ROS) or local temperature increase upon irradiation of a photosensitizer (PS) to realize the therapeutic action. Phototherapies offer unique advantages compared to conventional methods; thus, they are highly promising and popular. One of the design principles followed in new generation PSs is to build activity-based PSs, which stay inactive before getting activated by disease-associated stimuli. These activatable PSs dramatically improve the selectivity and efficacy of the therapy. In this review, we summarize small molecule and nanomaterial-based PDT and PTT agents that are activated selectively by H2S to initiate their cytotoxic effect. We incorporate single mode PDT and PTT agents along with synergistic and/or multimodal photosensitizers that can combine more than one therapeutic approach. Additionally, H2S-responsive theranostic agents, which offer therapy and imaging at the same time, are highlighted. Design approaches, working principles, and biological applications for each example are discussed in detail.

Directional conjugation of Trop2 antibody to black phosphorus nanosheets for phototherapy in orthotopic gastric carcinoma

Tumor-associated calcium signal transducer 2 (Trop2) is highly specific expressed in gastric carcinoma (GC). The combination of Trop2 antibody and phototherapy agents could exhibit synergetic antitumor activity. Black phosphorus nanosheets (BP) are covalently modified with Trop2 IgG antibodies via heterobifunctional linker of polyethylene glycol (PEG). Then the Trop2 antibody was directionally conjugated to BP via Schiff base reaction between aldehyde group from oxidized Trop2 antibody and amino group of PEG. The Trop2-functionalzied BP can significantly increase the endocytosis of BP in Trop2-positive GC cells exhibiting a reinforced antitumor activity under near infrared (NIR) irradiation. More importantly, a murine orthotopic GC model demonstrates that Trop2 antibody modification can significantly promote the accumulation of BP at tumor tissues and strengthen antitumoral activity of phototherapy. Directional conjugation of Trop2 antibody to BP facilitates the BP with superior stability, tumor targeting ability and excellent anti-tumor activity under NIR irradiation without systemic toxicity.

Porphyrin-based porous organic polymer coated ZIF-8 nanoparticles as tumor targeted photosensitizer for combination cancer photodynamic/photothermal therapy

The issue of low tumor-targeting and easy aggregation of small-molecule photosensitizers (PSs), as well as the heterogeneity and complexity of tumor tissue, greatly limit the therapeutic efficiency of phototherapy. Herein, a porphyrin-based organic polymer (POP) coated zeolitic imidazolate framework-8 (ZIF-8) hybrid nanoparticles (POP@ZIF-8) was developed, for delivering photosensitizer (porphyrin-based POP) specifically into tumor sites. The low-cost, biocompatible, tumor-specific POP@ZIF-8 with core-shell structure was prepared via a simple but efficient covalent surface-coating strategy, in which the pH-responsive ZIF-8 functioned as templates, finely controlling the nanometer size of the hybrid and ensuring targeted delivery of PSs to tumor tissue. Moreover, a direct covalently coated polymer-based PSs on ZIF-8 can better preserve optical properties compared to conventional physical adsorption methods. Under laser irradiation, the resulting hybridization not only efficiently converts light into local heat, causing severe photothermal damage to tumor tissue, but also synergistically promotes the production of strongly toxic 1O2, which exerts a photodynamic treatment on tumor sites. Therefore, this special POP@ZIF-8 hybrid presented a cooperatively enhanced synergistic photodynamic/photothermal anticancer efficacy, as demonstrated both the in vitro and in vivo assay, systematically. This study presents a practicable and reliable strategy to develop stable and high-efficiency cancer phototherapy agents which could simultaneously manipulate the structural characteristics and performance of targeted materials for promising noninvasive multi-mode anti-cancer.