Singlet Oxygen Delivery Research Articles

Superhydrophobic Dressing for Singlet Oxygen Delivery in Antimicrobial Photodynamic Therapy against Multidrug-Resistant Bacterial Biofilms.

The rise of antimicrobial resistance poses a critical public health threat worldwide. While antimicrobial photodynamic therapy (aPDT) has demonstrated efficacy against multidrug-resistant (MDR) bacteria, its effectiveness can be limited by several factors, including the delivery of the photosensitizer (PS) to the site of interest and the development of bacterial resistance to PS uptake. There is a need for alternative methods, one of which is superhydrophobic antimicrobial photodynamic therapy (SH-aPDT), which we report here. SH-aPDT is a technique that isolates the PS on a superhydrophobic (SH) membrane, generating airborne singlet oxygen (1O2) that can diffuse up to 1 mm away from the membrane. In this study, we developed a SH polydimethylsiloxane dressing coated with PS verteporfin. These dressings contain air channels called a plastron for supplying oxygen for aPDT and are designed so that there is no direct contact of the PS with the tissue. Our investigation focuses on the efficacy of SH-aPDT on biofilms formed by drug-sensitive and MDR strains of Gram-positive (Staphylococcus aureus and S. aureus methicillin-resistant) and Gram-negative bacteria (Pseudomonas aeruginosa and P. aeruginosa carbapenem-resistant). SH-aPDT reduces bacterial biofilms by approximately 3 log with a concomitant decrease in their metabolism as measured by MTT. Additionally, the treatment disrupted extracellular polymeric substances, leading to a decrease in biomass and biofilm thickness. This innovative SH-aPDT approach holds great potential for combating antimicrobial resistance, offering an effective strategy to address the challenges posed by drug-resistant wound infections.

A Targeting Singlet Oxygen Battery for Multidrug-Resistant Bacterial Deep-Tissue Infections.

Traditional photodynamic therapy (PDT) is dependent on externally applied light and oxygen, and the depth of penetration of these factors can be insufficient for the treatment of deep infections. The short half-life and short diffusion distance of reactive oxygen species (ROS) also limit the antibacterial efficiency of PDT. Herein, we designed a targeting singlet oxygen delivery system, CARG-Py, for irradiation-free and oxygen-free PDT. This system was converted to the "singlet oxygen battery" CARG-1 O2 and released singlet oxygen without external irradiation or oxygen. CARG-1 O2 is composed of pyridones coupled to a targeting peptide that improves the utilization of singlet oxygen in deep multidrug-resistant bacterial infections. CARG-1 O2 was shown to damage DNA, protein, and membranes by increasing the level of reactive oxygen inside bacteria; the attacking of multiple biomolecular sites caused the death of methicillin-resistant Staphylococcus aureus (MRSA). An in vivo study in a MRSA-infected mouse model of pneumonia demonstrated the potential of CARG-1 O2 for the efficient treatment of deep infections. This work provides a new strategy to improve traditional PDT for irradiation- and oxygen-free treatment of deep infections while improving convenience of PDT.

A Targeting Singlet Oxygen Battery for Multidrug‐Resistant Bacterial Deep‐Tissue Infections

AbstractTraditional photodynamic therapy (PDT) is dependent on externally applied light and oxygen, and the depth of penetration of these factors can be insufficient for the treatment of deep infections. The short half‐life and short diffusion distance of reactive oxygen species (ROS) also limit the antibacterial efficiency of PDT. Herein, we designed a targeting singlet oxygen delivery system, CARG‐Py, for irradiation‐free and oxygen‐free PDT. This system was converted to the “singlet oxygen battery” CARG‐1O2 and released singlet oxygen without external irradiation or oxygen. CARG‐1O2 is composed of pyridones coupled to a targeting peptide that improves the utilization of singlet oxygen in deep multidrug‐resistant bacterial infections. CARG‐1O2 was shown to damage DNA, protein, and membranes by increasing the level of reactive oxygen inside bacteria; the attacking of multiple biomolecular sites caused the death of methicillin‐resistant Staphylococcus aureus (MRSA). An in vivo study in a MRSA‐infected mouse model of pneumonia demonstrated the potential of CARG‐1O2 for the efficient treatment of deep infections. This work provides a new strategy to improve traditional PDT for irradiation‐ and oxygen‐free treatment of deep infections while improving convenience of PDT.

Back Cover: Targeted Singlet Oxygen Delivery: A Bioorthogonal Metabolic Shunt Linking Hypoxia to Fast Singlet Oxygen Release (Angew. Chem. Int. Ed. 47/2022)

Back Cover: Targeted Singlet Oxygen Delivery: A Bioorthogonal Metabolic Shunt Linking Hypoxia to Fast Singlet Oxygen Release (Angew. Chem. Int. Ed. 47/2022)

Rücktitelbild: Targeted Singlet Oxygen Delivery: A Bioorthogonal Metabolic Shunt Linking Hypoxia to Fast Singlet Oxygen Release (Angew. Chem. 47/2022)

Rücktitelbild: Targeted Singlet Oxygen Delivery: A Bioorthogonal Metabolic Shunt Linking Hypoxia to Fast Singlet Oxygen Release (Angew. Chem. 47/2022)

Targeted Singlet Oxygen Delivery: A Bioorthogonal Metabolic Shunt Linking Hypoxia to Fast Singlet Oxygen Release

AbstractSinglet oxygen can be generated by thermal cycloreversion of aromatic endoperoxides. However, for any practical potential of chemically generated singlet oxygen within a therapeutic context, the time and place of the release of this cytotoxic species must be tightly regulated. We now show that using a bimodular design with a hypoxia responsive unit and fluoride‐triggered endoperoxide unit, a bioorthogonal metabolic shunt can be established, where an enzymatically generated submicromolar fluoride signal plays a crucial role. Thus, cellular nitroreductase is repurposed in a bioorthogonal enzymatic activity, where it releases fluoride ions upon the reduction of a targeted compound. The fluoride ions released in the initial reaction remove the silyl stopper, yielding a highly accelerated release of singlet oxygen. The result is a remarkable difference in cytotoxicity between hypoxic and normoxic conditions as evidenced by microscopy, viability assays and the use of control compounds.

Targeted Singlet Oxygen Delivery: A Bioorthogonal Metabolic Shunt Linking Hypoxia to Fast Singlet Oxygen Release.

Singlet oxygen can be generated by thermal cycloreversion of aromatic endoperoxides. However, for any practical potential of chemically generated singlet oxygen within a therapeutic context, the time and place of the release of this cytotoxic species must be tightly regulated. We now show that using a bimodular design with a hypoxia responsive unit and fluoride-triggered endoperoxide unit, a bioorthogonal metabolic shunt can be established, where an enzymatically generated submicromolar fluoride signal plays a crucial role. Thus, cellular nitroreductase is repurposed in a bioorthogonal enzymatic activity, where it releases fluoride ions upon the reduction of a targeted compound. The fluoride ions released in the initial reaction remove the silyl stopper, yielding a highly accelerated release of singlet oxygen. The result is a remarkable difference in cytotoxicity between hypoxic and normoxic conditions as evidenced by microscopy, viability assays and the use of control compounds.

Degradation of amyloid peptide aggregates by targeted singlet oxygen delivery from a benzothiazole functionalized naphthalene endoperoxide.

Aggregate structures formed by amyloid-β (Aβ) are correlated with the progression of pathogenesis in Alzheimer's disease. Previous works have shown that photodynamic photosensitizers were effective in oxidatively degrading amyloid-β aggregates and thus decreasing their cytotoxicity under various conditions. In this work, we designed and synthesized a benzothiazole-naphthalene conjugate, with high level of structural analogy to Thioflavin T which is known to have high affinities for the amyloid peptide aggregates. The endoperoxide form (BZTN-O2) of this compound, which releases singlet oxygen with a half-life of 77 minutes at 37 °C, successfully inhibited and/or reversed amyloid aggregation. The endoperoxide is capable of singlet oxygen release without any need for light, and its charge-neutral form could allow blood-brain barrier (BBB) permeability. The therapeutic potential of such endoperoxide compounds with amyloid binding affinity is exciting.

Superhydrophobic Photosensitizers: Airborne 1O2 Killing of an in Vitro Oral Biofilm at the Plastron Interface.

Singlet oxygen is a potent agent for the selective killing of a wide range of harmful cells; however, current delivery methods pose significant obstacles to its widespread use as a treatment agent. Limitations include the need for photosensitizer proximity to tissue because of the short (3.5 μs) lifetime of singlet oxygen in contact with water; the strong optical absorption of the photosensitizer, which limits the penetration depth; and hypoxic environments that restrict the concentration of available oxygen. In this article, we describe a novel superhydrophobic singlet oxygen delivery device for the selective inactivation of bacterial biofilms. The device addresses the current limitations by: immobilizing photosensitizer molecules onto inert silica particles; embedding the photosensitizer-containing particles into the plastron (i.e. the fluid-free space within a superhydrophobic surface between the solid substrate and fluid layer); distributing the particles along an optically transparent substrate such that they can be uniformly illuminated; enabling the penetration of oxygen via the contiguous vapor space defined by the plastron; and stabilizing the superhydrophobic state while avoiding the direct contact of the sensitizer to biomaterials. In this way, singlet oxygen generated on the sensitizer-containing particles can diffuse across the plastron and kill bacteria even deep within the hypoxic periodontal pockets. For the first time, we demonstrate complete biofilm inactivation (>5 log killing) of Porphyromonas gingivalis, a bacterium implicated in periodontal disease using the superhydrophobic singlet oxygen delivery device. The biofilms were cultured on hydroxyapatite disks and exposed to active and control surfaces to assess the killing efficiency as monitored by colony counting and confocal microscopy. Two sensitizer particle types, a silicon phthalocyanine sol-gel and a chlorin e6 derivative covalently bound to fluorinated silica, were evaluated; the biofilm killing efficiency was found to correlate with the amount of singlet oxygen detected in separate trapping studies. Finally, we discuss the applications of such devices in the treatment of periodontitis.

Theoretical mechanistic study of self-sensitized photo-oxygenation and singlet oxygen thermal release in a dimethyldihydropyrene derivative

The self-sensitized photo-oxygenation and singlet oxygen thermal release mechanisms in a pyridinium-substituted dimethyldihydropyrene (DHP) derivative have been investigated using quantum chemical calculations. First, the main photophysical pathway for intersystem crossing was identified, allowing the production of a DHP triplet state. Second, the energy transfer pathway between this triplet state and the oxygen triplet ground state was computed revealing a very efficient route for the photosensitized generation of singlet oxygen. Finally, the thermal pathway for the formation of a metacyclophanediene endoperoxide and the singlet oxygen release was characterized. A concerted and a stepwise mechanism were identified, the first one being lower in energy. All these results are consistent with recent experimental results and confirm that this type of system could be attractive oxygen carriers and singlet oxygen delivery agents.

Rose Bengal incorporated in mesostructured silica nanoparticles: structural characterization, theoretical modeling and singlet oxygen delivery.

Rose Bengal (RB), a xanthene dye, incorporated into mesostructured silica nanoparticles (MSNs) exhibits efficient singlet oxygen ((1)O2) generation when illuminated with 540 nm green light which is particularly promising for PDT applications. Several systems with different RB loadings were synthesized and fully characterized by means of spectroscopic techniques in combination with a computational study, to optimize the amount of RB in order to avoid the formation of aggregates that is detrimental for a high (1)O2 delivery.

Toward singlet oxygen delivery at a measured rate: a self-reporting photosensitizer.

A Bodipy-based energy transfer cassette with a singlet oxygen reactive linker between the donor and acceptor modules has an interesting emergent property, if the acceptor module is also a photosensitizer. Singlet oxygen produced by the photosensitizer reacts rapidly with the molecule itself to liberate the energy donor, resulting in an enhanced fluorescence emission. The result is a self-reporting photosensitizer providing an assessment of the singlet oxygen production rate under the operational conditions.

Silica nanoreactors from silylated riboflavin for efficient singlet oxygen delivery.

Silylation of riboflavin allowed its incorporation into spherical SiO2 nanoparticles that were able to generate singlet oxygen and oxidize human serum albumin while conferring riboflavin remarkable photostability.

A Fiberoptic (Photodynamic Therapy Type) Device with a Photosensitizer and Singlet Oxygen Delivery Probe Tip for Ovarian Cancer Cell Killing

A portable "fiber optic-based sensitizer delivery" (FOSD) device has been developed and studied. Before there might be success in photodynamic therapy (PDT) and antibacterial ambitions, an understanding of basic factors on device performance was needed. Thus, the device was examined for the localized delivery of sensitizer molecules in ovarian cancer cells and production of high concentrations of singlet oxygen for their eradication in vitro. The device tip releases stored pheophorbide by attack of singlet oxygen from sensitized oxygen gas delivered through the hollow fiber using 669 nm laser light. The performance of the device was enhanced when configured with a fluorosilane tip by virtue of its Teflon-like property compared with a conventional glass tip (greater sensitizer quantities were photoreleased and laterally diffused, and greater amounts of ovarian OVCAR-5 cancer cells were killed). No cell damage was observed at 2.2 N of force applied by the probe tip itself, an amount used for many of the experiments described here.

Abstract 2481: Synthesis and characterization of PEGylated chlorin e6 sensitizers for the photodynamic killing of human ovarian cancer cells.

Abstract Pegylated chlorin e6 photosensitizers have been synthesized with triethylene glycol attached at the ester bond(s) for a 1:1 conjugate, a 2:1 conjugate, and a 3:1 conjugate. These chlorin sensitizers were studied for hydrolytic stability and solubility. Our studies included an analysis of ovarian OVCAR-5 cancer cell uptake, localization, and phototoxicity. Because of our interest in fiber-based photosensitizer and singlet oxygen delivery methods, desirable aspects of the 3:1 chlorin e6 conjugate make it a potential sensitizer for incorporation into a fiber optic device, particularly in the area of ovarian cancer photodynamic therapy. Citation Format: Ashwini Ghogare, Goutam Ghosh, Stanley Kimani, Dorota Bartusik, Benjamin Rudshteyn, Tayyaba Hasan, Alexander Greer. Synthesis and characterization of PEGylated chlorin e6 sensitizers for the photodynamic killing of human ovarian cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2481. doi:10.1158/1538-7445.AM2013-2481

Singlet Oxygen Delivery Through the Porous Cap of a Hollow-Core Fiber Optic Device

The development of the first photosensitizer/fiber optic device is reported. An oxygen-flowing, fiber-capped configuration is used for the application of heterogeneous, spatially confined singlet oxygen delivery in aqueous media. This is a unique device, unlike other heterogeneous photosensitizers, in which local concentrations of singlet oxygen can be delivered via introduction and withdrawal of the fiber tip.

Treatment of Verrucae Vulgaris and Molluscum Contagiosum with Photodynamic Therapy

The use of 5-aminolevulinc acid photodynamic therapy in the treatment of recalcitrant verrucae vulgaris and in the treatment of recalcitrant molluscum contagiosum has been shown to substantially reduce the lesion count and severity. Clinical research published in the medical literature and personal experience of both of the authors support the use of 5-aminolevulinc acid photodynamic therapy in appropriate individuals with recalcitrant verrucae vulgaris and molluscum contagiosum lesions. This article reviews the medical literature and identifies the various lasers and lights sources used to treat these conditions.

The embedding of meta-tetra(hydroxyphenyl)-chlorin into silica nanoparticle platforms for photodynamic therapy and their singlet oxygen production and pH-dependent optical properties.

This study relates to nanoparticle (NP) platforms that attach to tumor cells externally and only deliver singlet oxygen for photodynamic therapy (PDT) while conserving the embedded photosensitizers (PS). As a model, we demonstrate the successful embedding of the PS meta-tetra(hydroxyphenyl)-chlorin (m-THPC) in NP that are based on a sol-gel silica matrix and also show its positive effect on the singlet oxygen production. The embedding of m-THPC inside silica NP is accomplished by a modified Stöber sol-gel process, in which (3-aminopropyl)-triethoxysilane is introduced during the reaction. Singlet oxygen delivery by the targetable photodynamic NP exceeds that from free PS molecules. In the physiological pH range, there is no significant pH-induced decrease in the fluorescence of m-THPC embedded in silica NP, which might otherwise affect the efficiency of PDT.