Photosensitizers For Photodynamic Therapy Research Articles

Aggregation control of anionic pentamethine cyanine enabling excitation wavelength selective NIR-II fluorescence imaging-guided photodynamic therapy

Near-infrared (NIR)-II fluorescence imaging-guided photodynamic therapy (PDT) has shown great potential for precise diagnosis and treatment of tumors in deep tissues; however, its performance is severely limited by the undesired aggregation of photosensitizers and the competitive relationship between fluorescence emission and reactive oxygen species (ROS) generation. Herein, we report an example of an anionic pentamethine cyanine (C5T) photosensitizer for high-performance NIR-II fluorescence imaging-guided PDT. Through the counterion engineering approach, a triphenylphosphine cation (Pco) modified with oligoethylene glycol chain is synthesized and adopted as the counterion of C5T, which can effectively suppress the excessive and disordered aggregation of the resulting C5T-Pco by optimizing the dye amphipathicity and enhancing the cyanine-counterion interactions. Dynamic tuning of fluorescence characteristics and ROS generation is achieved at the aggregate level, resulting in an impressive type I ROS generation under 760 nm light irradiation, accompanied by efficient NIR-II fluorescence emission excited at 808 nm. As a result, excitation wavelength selective NIR-II fluorescence imaging-guided PDT has been successfully demonstrated for tumor diagnosis and therapeutics of female mice.

Near-Infrared Photothermal Conversion by Isocorrole and Phlorin Derivatives.

Photothermal therapy is a promising strategy for treating tumors and bacterial infections by using light irradiation to locally heat tissues. Metalloisoporphyrinoid materials have been investigated for their use as singlet oxygen photosensitizers for photodynamic therapy but remain underexplored as photothermal agents. Recently, two metallophlorin and two metalloisocorrole materials were found to have strong near-infrared absorbance, with low photoluminescent quantum yields, suggesting high rates of nonradiative decay. Here we demonstrate that when encapsulated into aggregated organic nanoparticles (a-Odots), these materials show high photothermal conversion efficiencies between 67.3 ± 8.4 and 75.7 ± 4.1%. When considered alongside their ability to generate singlet oxygen, these materials may show promise as agents for dual photothermal and photodynamic therapy.

Modulation of Donor in Purely Organic Triplet Harvesting AIE-TADF Photosensitizer for Image-guided Photodynamic Therapy.

Image-guided photodynamic therapy is acknowledged as one of the most demonstrative therapeutic modalities for cancer treatment because of its high precision, non-invasiveness, and improved imaging ability. A series of purely organic photosensitizers denoted as BTMCz, BTMPTZ, and BTMPXZ, have been designed and synthesized and are found to exhibit both thermally activated delayed fluorescence and aggregation-induced emission simultaneously. Experimental and theoretical studies are combined to reveal that modulation of the donor of the photosensitizer enables distinct thermally activated delayed fluorescence via a second-order spin-orbit perturbation mechanism involving lowest singlet charge-transfer and higher-lying triplet locally excited states, respectively. Further, different donor strengths and unique aggregations (H-, J- and X-type packings) greatly influence their color-tunable up-converted luminescence and endow them with superb dispersibility in water. The confocal microscopy-based cellular uptake study confirms the successful internalization of the nano-probes, while BTMCz enables the generation of reactive oxygen species (singlet oxygen) under white-light irradiation, enabling the efficient killing of cancer cells.

Photodynamic therapy photosensitizers and photoactivated chemotherapeutics exhibit distinct bioenergetic profiles to impact ATP metabolism.

Energy is essential for all life, and mammalian cells generate and store energy in the form of ATP by mitochondrial (oxidative phosphorylation) and non-mitochondrial (glycolysis) metabolism. These processes can now be evaluated by extracellular flux analysis (EFA), which has proven to be an indispensable tool in cell biology, providing previously inaccessible information regarding the bioenergetic landscape of cell lines, complex tissues, and in vivo models. Recently, EFA demonstrated its utility as a screening tool in drug development, both by providing insights into small molecule-organelle interactions, and by revealing the peripheral and potentially undesired off-target effects small molecules have within cells. Surprisingly, technologies to quantify cellular bioenergetics have not been systematically applied in phototherapy development, leaving open several questions about how the mechanism of action of a compound can impact essential cellular functions. Here, we utilized the Seahorse analyzer to address this question for photosensitizers (PSs) for photodynamic therapy (PDT) and contrast these systems to molecules that photo-release a ligand and thus act as photocages or photoactivated chemotherapeutics (PACT), intending to understand the influence these two classes of compounds have on cellular bioenergetics. EFA results show that acute treatment of A549 lung adenocarcinoma cells with PDT agents induces a quiescent bioenergetic response as a result of mitochondrial respiration shutdown. The loss of oxidative phosphorylation is followed by disruption of glycolysis, which occurs after an initial increase in glycolytic respiration is unable to compensate for the interruption of the electron transport chain (ETC). In contrast, the PACT agents tested had little impact on cellular respiration, and the minor inhibition of these metabolic processes was not related to the mechanism of action, as reflected by a lack of correlation with photoejection efficiency. Notably, a system capable of both generating 1O2 and photo-releasing a ligand exhibited the dominant profile of a PDT agent and induced the quiescent bioenergetic state, indicating potential implications on cellular bioenergetics for so-called dual-action agents. These findings are presented with the aim to provide the necessary groundwork for expanding the application and utility of EFA to phototherapeutics and to highlight the role of metabolic alterations in PDT.

Impact of the hydrophilic-lipophilic balance of free-base and Zn(II) tricationic pyridiniumporphyrins and irradiation wavelength in PDT against the melanoma cell lines.

The amphiphilic and asymmetric structure of porphyrins, when used as photosensitizers (PSs) for photodynamic therapy (PDT), has been shown through numerous previous studies to be a very important property that facilitates their entry into cells, which improves their efficiency in PDT. In this work, two groups of cationic AB3 pyridiniumporphyrins, free-base and chelated with Zn(II), both substituted with alkyl chains of various lengths, were studied in PDT on melanoma cell lines. The aim was to investigate the impact of hydrophilic-lipophilic balance and Zn(II) chelation, and the importance of matching the irradiation wavelength to the optical properties of the PS on in vitro PDT efficiency. Therefore, spectroscopic studies, singlet oxygen production and lipophilicity as well as cellular uptake, localization and cytotoxicity studies of the two series of porphyrins were performed. In both series of porphyrins, the longest alkyl chain (17C-atoms long) enables the greatest internalization of the PS. Chelation with Zn(II) resulted in better physicochemical properties, but slower cellular internalization. As expected, free-base porphyrins were more PDT efficient than their Zn(II) complexes after 30-min photoactivation by low-fluence (2mW/cm2) red light (643nm). However the use of orange light (606nm) with the same fluence rate was more suitable for Zn(II) porphyrins and resulted in similar overall toxicity to their free-base analogues with similar lipophilicity. Although the highest phototoxicity was achieved with the PSs carrying the longest alkyl chain, TMPyP3-C13H27 and Zn(II)-TMPyP3-C13H27 proved to be the most promising candidates for use in PDT as they exhibit high phototoxicity, but also greater selectivity towards melanoma cell lines (MeWo and A375) compared to fibroblasts (HDF).

Hafnium-Based Metal-Organic Framework Nanosystems Entrapping Squaraines for Efficient NIR-Responsive Photodynamic Therapy.

In this study, we present for the first time the incorporation of two distinct nonsymmetrical squaraines (SQ) into hierarchically porous Hafnium-based UiO-66 Metal-Organic Frameworks (MOFs), each functionalized with various moieties, for application as photosensitizers in photodynamic therapy. SQs are meticulously designed to feature COOH moieties for interaction with the MOF's metallic cluster and bromine atoms to enhance intersystem crossing and reactive oxygen species (ROS) production. The distinct central functionalizations, one with squaric acid and the other with a dicyanovinyl-substituted squaric acid derivative, result in unique geometric conformations. The latter, as well as the molecular size and density, have been analyzed by computational methods, facilitating the optimal design of MOF cavities for SQ accommodation. Our synthetic methodology involves the production of hierarchically porous Hf-MOFs that integrate both micro- and mesopores. The resultant SQ@MOF systems preserve photosensitizing properties, enhancing solubility and stability without compromising ROS generation or MOF structural integrity. As proof of concept, in vitro evaluations against PANC-1 cells were evaluated, demonstrating the cytocompatibility of SQ@MOFs in the dark up to concentrations of 200 μg mL-1. Photoactivity is assessed using a statistical multivariate design, enabling identification of the SQ@MOF system with the highest phototoxicity and determination of the variables that significantly influence phototoxicity.

Aggregation assisted enhancement of singlet oxygen generation by 4-ethynylphenyl substituted porphyrin photosensitizer for photodynamic therapy.

Modulating the photophysical properties of photosensitizers is an effective approach to enhance singlet oxygen generation for photodynamic therapy. Porphyrins are the most widely used photosensitizers due to their biocompatible nature. Aggregation-induced emission (AIE) characteristics of photosensitizers are one of the advantageous features that will enhance fluorescence, intersystem crossing, and efficient triplet state generation. Herein, we demonstrate two glycosylated porphyrin photosensitizers, ZnGEPOH (with two ethynyl groups) and ZnGPOH (without two ethynyl groups), which exhibit AIE. Detailed studies revealed that ZnGEPOH exhibited a two-fold increase in singlet oxygen production than ZnGPOH due to AIE. The photo-cytotoxicity of ZnGPOH and ZnGEPOH were evaluated using cancer cell lines A549 and AGS. ZnGEPOH shows superior photo-cytotoxicity with cell viability of 21% and 19% for A549 and AGS, respectively, at 250 μg/mL concentration in 48 h. Moreover, ZnGEPOH exhibits minimal photo-cytotoxicity towards the control cell line HEK 293.

Cytodestructive Effects of Photodynamic Exposure in Primary Cultures of Malignant Glioma Cells

Background. Photodynamic therapy (PDT) is a promising adjuvant method for the treatment of malignant gliomas (MG), including tumors with continued growth and tumor recurrences. For the clinical application of PDT, it is important to substantiate the effectiveness of the cytodestructive effect of the combined use of laser irradiation (LI) and photosensitizer (PS). Objective. To evaluate the cytodestructive effects of photodynamic exposure with the use of PS chlorine E6 on primary MG cell cultures. Methods. Primary cell cultures were obtained from samples of biopsy material from patients (n = 6) with a veri­fied diagnosis: 3 primary tumors (1 case of diffuse astrocytoma, NOS (G3), 1 – glioblastoma (GB), NOS (G4), 1 – gliosarcoma (G4)) and 3 – with continued tumor growth (1 – diffuse astrocytoma, NOS (G3), 1 – oligo­dendroglioma, NOS (G3) and 1 – GB, NOS (G4). Groups of cell cultures included: 1) control – cultured in a standard nutrient medium and experimental; 2) cultured with the addition of chlorine E6 (2.0 mg/ml); 3) cultivated without the addition of PS and subjected to LI; 4) cultivated with the addition of chlorine E6 and subsequent exposure to LI. After 24 h, morphological and morpho­metric studies were carried out. Results. The primary MG cultures were characterized by different growth dynamics; mitotic activity of tumor cells varied from the highest rate in the culture of primary GB to lower values – in cultures of recurrent GB and primary astrocytoma and gliosarcoma, and the lowest – in cultures of continued growth of astrocytoma and oligodendroglioma after combined treatment. Direct exposure to chlorine E6 and LI reduced the total number of cells in the culture and their mitotic activity. The greatest cytodestructive effect was achieved with the combined effect of chlorine E6 and LI: the effective dose in the case of primary astrocytoma cells is 10 J/cm2 in pulse mode; for cells of primary GB and gliosarcoma, recurrent astrocytoma and oligodendro­glioma, the effective dose is 25 J/cm2 in pulsed mode. In the case of GB cells, continued growth, a dose of 25 J/cm2 is effective for both continuous and pulsed modes of LI. Conclusions. Primary cell cultures of MG obtained directly from tumor tissue are an adequate model for evaluating the effectiveness of the cytodestructive effect of the combined use of LI and PS for PDT.

Divulging the potency of naturally derived photosensitizers in green PDT: an inclusive review Of mechanisms, advantages, and future prospects.

Photodynamic Therapy (PDT) offers a minimally invasive approach for treating various health conditions, employing a photosensitizer (PS) and specific light. Recent enhancements make PDT outpatient-friendly and less discomforting. Effectiveness hinges on selecting the appropriate PS. This article delves into natural and synthetic PSs, emphasizing the rising interest in natural alternatives for their safety. It explores their mechanisms, characteristics, and applications, offering insights into their potential contributions to advancing PDT. This extensive review delves into the preclinical and clinical landscape of natural PSs for PDT, shedding light on their diverse applications and promising outcomes. Compounds like curcumin, piperine, riboflavin, psoralen, hypericin, and others show significant potential in preclinical in vitro studies across various cell lines. In vivo, these photosensitizers prove effective against skin tumors, carcinomas, and sarcomas, inducing apoptosis, autophagy, and ROS generation for therapeutic efficacy. The review underscores the critical role of proper dosing and monitoring in balancing therapeutic benefits and risks. It highlights the advantages and limitations of natural PSs, emphasizing their specific targeting, bioavailability, and limited side effects. The future of PDT holds promising breakthroughs, taking from some evidence like Bergamot oil in nanostructured lipid carriers for dermatological conditions. Second-generation photosensitizer Tookad shows potential in prostate cancer treatment, while Tripterygium wilfordii Hook. F. emerges as an antimicrobial PDT source etc. Thus, environmental concerns in PDT prompt a shift to plant extracts for PS purification. The evidence-supported focus on natural PSs establishes this article as a key resource for advancing natural compounds in PDT and their therapeutic applications.

Metal Doping Enabling Defective CoMo-Layered Double Hydroxide Nanosheets as Highly Efficient Photosensitizers for NIR-II Photodynamic Cancer Therapy.

Photodynamic therapy (PDT) is attracting widespread attention as a promising strategy for tumor treatment. However, the efficacy of PDT is severely limited by the insufficient tissue penetration depth of the light source and low reactive oxygen species (ROS) generation efficiency. Herein, the metal doping strategy is reported to construct a series of defect-rich M-doped amorphous CoMo-layered double hydroxide (a-M-CoMo-LDH, M = Mn, Cu, Al, Ni, Mg, Zn) photosensitizers (PSs) for NIR-II PDT. Especially, M-doped CoMo-LDH nanosheets are synthesized through a simple hydrothermal method and then etched by acid treatment to prepare defect-rich a-M-CoMo-LDH nanosheets. Under NIR-II 1270 nm laser irradiation, the defect-rich a-Zn-CoMo-LDH nanosheets exhibit the optimal PDT performance compared with other a-M-CoMo-LDH nanosheets, and also possess much higher ROS production activity (3.9 times) than that of the pristine a-CoMo-LDH, with a singlet oxygen quantum yield up to 1.86, which is the highest among all the reported PSs. After polyethylene glycol (PEG) modification, the a-Zn-CoMo-LDH-PEG nanosheets can function as an effective inorganic PS for PDT, effectively inducing cell apoptosis in vitro and eradicating tumors in vivo. Notably, transcriptome sequencing analysis and further molecular validation highlight the critical role of the apoptotic/p53/AMPK/oxidative phosphorylation signaling pathways in a-Zn-CoMo-LDH-PEG-induced cancer cell apoptosis.

Exploring the potential of 7,4′-di(diethylamino)flavylium as a novel photosensitizer for topical photodynamic therapy of skin cancer

Photodynamic therapy (PDT) is a minimally invasive therapeutic approach that has shown promising results in recent years, particularly in the dermatological clinical treatment of several pathologies, including neoplastic skin diseases. In light of the recent discovery of the photosensitizing properties of a water-soluble group of amino-based flavylium dyes, research efforts have led to the development of a novel synthetic dye with two diethylamino moieties in its structure, 7,4’-di(diethylamino)flavylium (7,4′diN(Et)2). This dye was tested as a potential photosensitizer for PDT of skin cancer. A single light dose of 22.5 J/cm2 efficiently killed SCC-25 (squamous cell carcinoma) and A375 (melanoma) cells, reducing cellular viability by more than 80% in the presence of the flavylium at 0.75 µM. Meanwhile, the negligible cellular toxicity of the dye in the absence of light stimulus points out a wide and safe therapeutic window. Interestingly, significant light-induced toxicity effects were still observed after washing out the compound before cell irradiation. Moreover, out of the three prototype flavylium-loaded hydrogels, each one based on a different polymer (Carbomer, Caesalpinia Spinosa Gum and Hydroxypropyl methyl cellulose), carbomer-based formulation stood out for its substantial absorbance and fluorescence increment and enhanced1O2 photogeneration activity compared to the flavylium in aqueous solution. The findings of this study provide valuable insights concerning the potential of this flavylium dye as a candidate for photodynamic therapy of skin cancer and strongly support the need for further testing in more advanced biological settings to fully assess its efficacy and safety.

Photochemical and Sono-Photochemical Studies of Zn (II) Porphyrin-conjugated Chitosan Hydrogels for Enhanced Singlet Oxygen Generation

This study explores the synthesis, characterization, photochemical, and sono-photochemical properties of covalently conjugated porphyrin-chitosan hydrogels for potential application in photodynamic therapy (PDT) and sono-photodynamic therapy (SPDT). The efficient production of singlet oxygen, a crucial reactive oxygen species (ROS) in these therapies, was investigated. Zinc(II) porphyrins 1 and 2 were synthesized by metal insertion to free based porphyrins and covalently linked to chitosan via Schiff-base reaction to produce chitosan hydrogel CS-1 and CS-2 (conjugation via phenylacetylene spacer). The synthesized compounds were characterized using standard spectroscopic techniques, confirming successful conjugation. Scanning electron microscopy (SEM) analysis demonstrating the homogeneous distribution of porphyrins within the hydrogel matrix. Photophysical and photochemical properties, including ground state absorption and singlet oxygen generation, were evaluated for both porphyrin complexes and chitosan-conjugated hydrogels in DMSO. The porphyrin-hydrogel structures showed superior singlet oxygen generation efficiency. Sono-photochemical studies showed further enhanced singlet oxygen generation, with the highest quantum yield (ΦΔ= 0.81) observed for the chitosan hydrogel CS-2. The results demonstrated enhanced singlet oxygen generation in the hydrogel structures, particularly under simultaneous ultrasound and light irradiation, indicating their potential efficacy in PDT and SPDT applications. Additionally, photo degradation studies revealed the stability of the synthesized compounds under light irradiation. These findings highlight the potential of porphyrin-conjugated chitosan hydrogels as effective photosensitizers for PDT and SPDT applications.

Visualization of Stress Fiber Formation Induced by Photodynamic Therapy with Porphylipoprotein.

We investigated stress fiber formation induced by photodynamic therapy (PDT) with porphylipoprotein (PLP) by observing actin filaments by super-resolution confocal microscopy and measuring the cellular elastic modulus by atomic force microscopy. We identified different intracellular mechanisms of stress fiber formation between RGM1 epithelial cells, which were derived from rat gastric mucosa, and RGK1 cells, which were cancer-like mutants of RGM1. Our findings show that when PLP is used as a photosensitizer in PDT, it selectively induces necrosis in tumors with minimal impact on the surrounding normal tissues, as it is less likely to cause blood flow obstruction.

Hypoxia-responsive liposome enhances intracellular delivery of photosensitizer for effective photodynamic therapy

Liposomes, especially polyethylene glycol (PEG)-modified long-circulating liposomes, have been approved for market use, due to good biocompatibility, passive tumor targeting, and sustained drug release. PEG-modified long-circulating liposomes address issues such as poor stability and rapid clearance by the reticuloendothelial system. However, they still face challenges like hindering drug uptake by tumor cells and preventing tumor penetration. Inspired by the hypoxic tumor microenvironment, we constructed a hypoxia-responsive liposome (PAO-L) to enhance the intracellular uptake and photodynamic therapy (PDT) effect of chlorin e6 (Ce6). The intelligent hypoxia-cleavable PEG-AZO-OA (PAO) was prepared by coupling PEG and octadecylamine (OA) to hypoxia-sensitive azobenzene-4,4′-dicarboxylic acid (AZO) through amide reaction. The synthesized PAO was further incorporated into Ce6-loaded liposomes to enhance the circulation stability, while promote the tumor penetration and internalization by the responsive shedding of PEG from liposome surface upon reaching the hypoxic tumor tissue. PAO-L mediated PDT significantly inhibited the growth of B16F10 and 4T1 tumors, as well as lung metastasis of 4T1 breast cancer. The excellent therapeutic effect and good tolerability make PAO-L a promising candidate for enhanced PDT.

Rechargeable Afterglow Superclusters for NIR-Excitable Repetitive Phototherapy.

Afterglow luminescence has attracted increasing attention due to its prolonged emission, reduced autofluorescence, and minimized photodamage. However, persistent luminescence typically requires high-energy excitation (e.g., ultraviolet and visible light), which has limited tissue penetration. Herein, we have developed a one-pot surface segregation strategy to construct NIR-excitable afterglow superclusters (UCZG-SCs) by modularly assembling spinel-phase afterglow nanoparticles (Zn1.1Ga1.8Ge0.1O4:Cr3+) and hexagonal-phase upconversion nanoparticles (NaYF4:Yb,Tm@NaLuF4:Y). Since the proposed methodology does not require crystal lattice similarity, it enables fabrication of various NIR-excitable persistent superclusters with great flexibility in size, composition, and luminescent profiles. As a proof of concept, an injectable persistent implant is established by embedding UCZG-SCs in the oleosol of poly(lactic-co-glycolic acid)/N-methylpyrrolidone, which serves as an inner-body lamp to excite photosensitizers for photodynamic therapy. With its excellent charging-recharging stability, a repetitive phototherapy under periodic 980 nm light illumination is accomplished, which significantly improves phototherapeutic efficiency and restrains tumor growth.

Multi-Spectroscopic and Molecular Modeling Studies of Interactions Between Anionic Porphyrin and Human Serum Albumin.

The subject of this study is the interaction between 5,10,15,20-tetrakis (4-sulfonatophenyl)-porphyrin (TSPP), a potential photosensitizer for photodynamic therapy (PDT) and radiotherapy, and human serum albumin (HSA), a crucial protein in the body. The main objective was to investigate the binding mechanisms, structural changes, and potential implications of these interactions for drug delivery and therapeutic applications. Spectroscopic techniques and computational methods were employed to investigate the mechanism and effects of TSPP binding by HSA. The results suggest the possibility of simultaneous binding of three TSPP ions at binding sites of different affinity within albumin. The estimated values of the binding constant Kb for these sites were in the range of 0.6 to 6.6 μM-1. Laser flash photolysis indicated the stabilization of TSPP in the HSA structure, which resulted in prolonged lifetimes of the excited states (singlet and triplet) of porphyrin. Circular dichroism analysis was used to assess the changes in the secondary and tertiary structures of HSA upon TSPP binding. An analysis of the molecular docking results allowed us to identify the preferred TSPP binding sites within HSA and provided information on the specific interactions of amino acids involved in the stabilization of TSPP-HSA complexes. The estimated free energy of the binding of porphyrin at the three most favorable docking sites found in the HSA structure that was considered native were in the range of -80 to -41 kcal/mol. Finally, thermal unfolding studies showed that TSPP increased the stability of the secondary structure of albumin. All these findings contribute to the understanding of the interactions between TSPP and HSA, offering valuable insights for the development of novel cancer therapy approaches.

Photophysics and Excited State Reactions of [Ru(bpy)2dppn]2+: A Computational Study.

In this work, we used DFT and TD-DFT in the investigation of the structural parameters and photophysics of the complex [Ru(bpy)2dppn]2+ (dppn=benzo[i]-dipyrido[3,2-a:2',3'-c]phenazine) in water, and its suitability as a photosensitizer (PS) in photodynamic therapy (PDT). For that, the thermodynamics of electron transfer (ET) and energy transfer (ENT) reactions in the excited state with molecular oxygen and guanosine-5'-monophosphate (GMP) were investigated. The overall intersystem crossing (ISC) rate constant was approximately 1012 s-1, indicating that this process is highly favorable, and the triplet excited states are populated. The triplet excited states are known to lead to photoreactions between the PS and species of the medium or directly with nucleobases. Here, we show that the Ru-dppn complex can react favorably to oxidize the GMP and generate singlet oxygen. Furthermore, this complex can also act as an intercalator between DNA base pairs and undergo dual-channel reactions. It has been proposed that the T2 excited state is responsible for oxidizing the GMP, but we show that T1 is thermodynamically capable of undergoing the same reaction. In this sense, docking simulations were carried out to investigate further the interactions of the Ru-dppn complex with a DNA fragment.

The Latest Applications of Carbon-Nitride-Based Materials for Combination Treatment of Cancer.

Carbon-nitride-based (CN-based) materials have shown great potential in combination therapy in recent years. Due to their outstanding biocompatibility, ease of modification, and adjustable band-gap position, CN-based materials can be applied as photosensitizers in photodynamic therapy (PDT) and light-driven water-splitting catalysts in gas therapy. After doping with other elements, the photocatalytic performance of CN-based materials will be enhanced, and more interesting functions will be obtained. In addition, the large specific surface area also promotes CN-based materials as drug carriers combined with other therapeutic modalities to achieve combination therapy. This Review analyzes and summarizes the latest research on CN-based materials in combined therapies, such as PDT with photothermal therapy (PTT), PDT with sonodynamic therapy (SDT), PDT with drug therapy, PDT with gene therapy, gas therapy with PDT, and bioimaging-guided combined therapy. In particular, the applications of CN-based materials in gas and gene combination therapy are summarized for the first time. Finally, the current challenges faced by CN-based materials in combination therapy are further discussed.

Anthracene-Based Endoperoxides as Self-Sensitized Singlet Oxygen Carriers for Hypoxic-Tumor Photodynamic Therapy.

Singlet oxygen is a crucial reactive oxygen species (ROS) in photodynamic therapy (PDT). However, the hypoxic tumor microenvironment limits the production of cytotoxic singlet oxygen through the light irradiation of PDT photosensitizers (PSs). This restriction poses a major challenge in improving the effectiveness of PDT. To overcome this challenge, researchers have explored the development of singlet oxygen carriers that can capture and release singlet oxygen in physiological conditions. Among these developments, anthracene-based endoperoxides, initially discovered almost 100 years ago, have shown the ability to generate singlet oxygen controllably under thermal or photo stimuli. Recent advancements have led to the development of a new class of self-sensitized anthracene-endoperoxides, with potential applications in enhancing PDT effects for hypoxic tumors. This review discusses the current research progress in utilizing self-sensitized anthracene-endoperoxides as singlet oxygen carriers for improved PDT. It covers anthracene-conjugated small organic molecules, metal-organic complexes, polymeric structures, and other self-sensitized nano-structures. The molecular structural designs, mechanisms, and characteristics of these systems will be discussed. This review aims to provide valuable insights for developing high-performance singlet oxygen carriers for hypoxic-tumor PDT.

Zinc phthalocyanine-bridged periodic mesoporous organosilica nanoparticle as biodegradable photosensitizer for photodynamic therapy

The development of efficient photosensitizers is vital for advancing photodynamic therapy (PDT), a non-invasive cancer treatment. Although zinc phthalocyanine (ZnPc) has garnered significant attention as a photosensitizer in preclinical studies, its clinical application is hindered by poor solubility and a tendency to aggregate, despite its high absorption coefficient and low dark toxicity. To address these challenges, we developed a novel ZnPc-conjugated periodic mesoporous organosilica (PMO) nanoparticle, which enhances the photosensitizer's solubility, photostability, and biodegradability. The PMO nanoparticles retained the characteristic mesoporous structure, exhibited strong fluorescence emission, and effectively generated singlet oxygen. In vitro studies using 4T1 cells, along with in vivo experiments on a tumor-bearing mouse model, demonstrated that under 675 nm laser irradiation, the ZnPc-PMO nanophotosensitizer induced reactive oxygen species, leading to significant inhibition of tumor growth. This ZnPc-bridged PMO nanophotosensitizer holds great promise for enhancing PDT efficacy and biocompatibility, offering a potential platform for multimodal phototherapeutic strategies.