The anti-cancer effect of series of strained photoactivatable Ru(II) polypyridyl complexes on non-small-cell lung cancer and triple negative breast cancer cells.

Ruthenium complexes have been recently reported as potential chemotherapeutic agents that offer tumor selectivity and low tumor resistance. This study investigates the photochemistry and the effect of four strained photoactivatable polypyridyl ruthenium(II) complexes on non-small-cell lung cancer (A549) and triple negative breast cancer (MDA-MB-231) cells. All four ruthenium(II) complexes, [Ru(bpy)2dmbpy]Cl2 (C1) where (bpy = 2,2'-bipyridine and dmbpy = 6,6'-dimethyl-2,2'-bipyridine), [Ru(phen)2dmbpy]Cl2 (C2) where (phen = 1,10-phenanthroline), [Ru(dpphen)2dmbpy]Cl2 (C3) (where dpphen = 4,7-diphenyl-1,10-phenanthroline) and [Ru(BPS)2dmbpy]Na2 (C4) where (BPS = bathophenanthroline disulfonate) eject the dmbpy ligand upon activation by blue light. Determination of the octanol-water partition coefficient (log P) revealed that C3 was the only lipophilic complex (log P = 0.42). LC-MS/MS studies showed that C3 presented the highest cellular uptake. The cytotoxic effect of the complexes was evaluated with and without blue light activation using WST-1 kit. Data indicated that C3 exhibited the highest cytotoxicity after 72 h (MDA-MB-231, IC50 = 0.73 µM; A549, IC50 = 1.26 µM) of treatment. The phototoxicity indices of C3 were 6.56 and 4.64 for MDA-MB-230 and A549, respectively. Upon light activation, C3 caused significant ROS production and induced apoptosis in MDA-MB-231 cells as shown by flow cytometry. It also significantly increased Bax/Bcl2 ratio and PERK levels without affecting caspase-3 expression. C3 exhibited poor dark toxicity (IC50 = 74 µM) on rat mesenchymal stem cells (MSCs). In conclusion, the physical property of the complexes dictated by the variable ancillary ligands influenced cellular uptake and cytotoxicity. C3 may be considered a promising selective photoactivatable chemotherapeutic agent that induces ROS production and apoptosis.

Umbelliferone Decorated Water-soluble Zinc(II) Phthalocyanines - In Vitro Phototoxic Antimicrobial Anti-cancer Agents.

In this contribution we report on the synthesis, characterization and application of water-soluble zinc(II) phthalocyanines, which are decorated with four or eight umbelliferone moieties for photodynamic therapy (PDT). These compounds are linked peripherally to zinc(II) phthalocyanine by a triethylene glycol linker attached to pyridines, leading to cationic pyridinium units, able to increase the water solubility of the system. Beside their photophysical properties they were analyzed concerning their cellular distribution in human hepatocyte carcinoma (HepG2) cells as well as their phototoxicity towards HepG2 cells, Gram-positive (S. aureus strain 3150/12 and B. subtilis strain DB104) and Gram-negative bacteria (E. coli strain UTI89 and E. coli strain Nissle 1917). At low light doses and concentrations, they exhibit superb antimicrobial activity against Gram-positive bacteria as well as anti-tumor activity against HepG2. They are even capable to inactivate Gram-negative bacteria, whereas the dark toxicity remains low. These unique water-soluble compounds can be regarded as all-in-one type photosensitizers with broad applications ranges in the future.

Halogenated Gallium Corroles:DNA Interaction and Photodynamic Antitumor Activity.

A series of halogenated gallium corroles were synthesized and characterized by UV-vis, HRMS, NMR, and FT-IR. The interaction between these gallium corroles and calf thymus DNA had been investigated by spectroscopic methods. These gallium corroles would interact with CT-DNA via an outside binding mode. The photodynamic antitumor activity in vitro of these gallium corroles toward different cell lines had also been tested. 3-Ga displayed low cytotoxicity to normal cells under both light and dark conditions but high phototoxicity to liver cancer cells HepG2. The vitro experiment results showed that 3-Ga could be efficiently absorbed by tumor cells. After light illumination, it may induce reactive oxygen species (ROS) and cause destruction of the mitochondrial membrane potential, which may finally trigger tumor cell apoptosis. Flow cytometry results showed that HepG2 cells were mainly distributed in the sub-G0 phase, which corresponds to cells with highly fragmented DNA or dead cells generally. This suggests that 3-Ga could lead to tumor cell apoptosis after light illumination.

Preparation, toxicity reduction and radiation therapy application of gold nanorods.

Gold nanorods (GNRs) have a broad application prospect in biomedical fields because of their unique properties and controllable surface modification. The element aurum (Au) with high atomic number (high-Z) render GNRs ideal radiosensitive materials for radiation therapy and computed tomography (CT) imaging. Besides, GNRs have the capability of efficiently converting light energy to heat in the near-infrared (NIR) region for photothermal therapy. Although there are more and more researches on GNRs for radiation therapy, how to improve their biocompatibility and how to efficiently utilize them for radiation therapy should be further studied. This review will focuse on the research progress regarding the preparation and toxicity reduction of GNRs, as well as GNRs-mediated radiation therapy.

Chronic facial eczema in sheep: description of gross and histological changes in the liver and association with serum gamma-glutamyltransferase activity at the time of sporidesmin intoxication.

AIMS: To determine the gross and histological changes developing in the liver of sheep 8 months after a single period of exposure to sporidesmin and to examine associations between the severity of gross and histological changes to the liver and the activity of gamma-glutamyltransferase (GGT) measured in serum in the sheep at the time of intoxication. METHODS: A group of 50 Romney ewes grazing a mixed ryegrass/white clover pasture were accidentally exposed to sporidesmin for up to 5 weeks. Seventeen sheep showed photosensitisation and four were subject to euthanasia. The remaining sheep were moved to safer pasture and a blood sample collected and analysed for serum GGT activity. The sheep were slaughtered 8 months later. Livers were classified into grossly normal, moderately affected, or severely affected and histology performed to assess portal fibrosis, biliary hyperplasia, portal inflammation, and hepatocellular necrosis. RESULTS: Serum GGT activity ranged from 59 to 1571 IU/L (reference range 32-70 IU/L). Thirteen of the 46 sheep developed clinical signs of facial eczema. However, at slaughter all except four sheep had grossly detectable changes to the shape of the liver including atrophy of the left lobe and the lateral part of the right lobe. Hypertrophy was typically limited to the medial part of the right lobe. In severely affected sheep the liver hypertrophy formed a nodular bulging mass. Changes in the liver shape were classified as severe in 25 and moderate in 17 sheep. Severely affected livers contained significantly more fibrosis than moderately affected livers (p = 0.001, Cliff's delta (d) = 0.68). While there was significantly greater fibrosis and biliary hyperplasia in the left than right lobes, histological changes were present throughout all samples taken of affected livers. Serum GGT activity taken during acute intoxication were correlated to subsequent fibrosis and biliary hyperplasia. CONCLUSIONS: Hepatic fibrosis develops in sheep after a single episode of sporidesmin intoxication, even in sheep with only mildly elevated GGT activity at the time of intoxication. Furthermore, the severity of the subsequent hepatic fibrosis was predicted by the degree of elevation of serum GGT activity during intoxication. CLINICAL RELEVANCE: More research is required to determine how the presence and severity of hepatic fibrosis affect animal production. However, if hepatic fibrosis does decrease production, the consistent development of fibrosis after sporidesmin ingestion reinforces the importance of avoiding exposure of livestock to sporidesmin. ABBREVIATIONS: GGT: Gamma-glutamyltransferase; d: Cliff's delta.

Bioorthogonal Turn-On BODIPY-Peptide Photosensitizers for Tailored Photodynamic Therapy.

Photodynamic therapy (PDT) leads to cancer remission via the production of cytotoxic species under photosensitizer (PS) irradiation. However, concomitant damage and dark toxicity can both hinder its use. With this in mind, we have implemented a versatile peptide-based platform of bioorthogonally activatable BODIPY-tetrazine PSs. Confocal microscopy and phototoxicity studies demonstrated that the incorporation of the PS, as a bifunctional module, into a peptide enabled spatial and conditional control of singlet oxygen (1 O2 ) generation. Comparing subcellular distribution, PS confined in the cytoplasmic membrane achieved the highest toxicities (IC50 =0.096±0.003 µm) after activation and without apparent dark toxicity. Our tunable approach will inspire novel probes towards smart PDT.

2-Naphthol Moiety of Neocarzinostatin Chromophore as a Novel Protein-Photodegrading Agent and Its Application as a H2 O2 -Activatable Photosensitizer.

A 2-naphthol derivative 2 corresponding to the aromatic ring moiety of neocarzinostatin chromophore was found to degrade proteins under photo-irradiation with long-wavelength UV light without any additives under neutral conditions. Structure-activity relationship studies of the derivative revealed that methylation of the hydroxyl group at the C2 position of 2 significantly suppressed its photodegradation ability. Furthermore, a purpose-designed synthetic tumor-related biomarker, a H2 O2 -activatable photosensitizer 8 possessing a H2 O2 -responsive arylboronic ester moiety conjugated to the hydroxyl group at the C2 position of 2, showed significantly lower photodegradation ability compared to 2. However, release of the 2 from 8 by reaction with H2 O2 regenerated the photodegradation ability. Compound 8 exhibited selective photo-cytotoxicity against high H2 O2 -expressing cancer cells upon irradiation with long-wavelength UV light.

Novel Type of Water-Soluble Photosensitizer from Trichoderma reesei for Photodynamic Inactivation of Gram-Positive Bacteria.

Antimicrobial photodynamic therapy (APDT) is a promising alternative to traditional antibiotics for the treatment of bacterial infections, which inactivates a broad spectrum of bacteria. However, many traditional photosensitizers (PSs) are hydrophobic with poor water solubility and easy aggregation. On the other hand, some light sources such as ultraviolet (UV) have poor penetration and high cytotoxicity. Both issues lead to undesired photodynamic therapy efficacy. To overcome these issues, we develop a novel water-soluble natural PS (sorbicillinoids) obtained by microbial fermentation using recombinant filamentous fungus Trichoderma reesei. Sorbicillinoids could effectively generate singlet oxygen (1O2) under UV light irradiation and ultimately display photoinactivation activity on Gram-positive bacteria including Staphylococcus aureus, Bacillus subtilis, and Micrococcus luteus but not Gram-negative ones such as Escherichia coli and Proteus vulgaris. Sorbicillinoids were found to enter S. aureus but not E. coli. S. aureus treated with sorbicillinoids and UV light displayed high levels of intracellular reactive oxygen species (ROS), notable DNA photocleavage, and compromised cell semipermeability without overt cell membrane disruption, none of which was found in the treated E. coli. All these contribute to the sorbicillinoid-based photoinactivation of Gram-positive bacteria. Moreover, the dark toxicity and phototoxicity on mammalian cells or hemolysis activity of sorbicillinoids is negligible, showing its excellent biocompatibility. This study expands the utilization of UV light for surface sterilization to disinfection in solution. Therefore, sorbicillinoids, a type of secondary metabolite from fungus, have a promising future as a new PS for APDT using a nontoxic dose of UV irradiation.

Specific Targeting, Imaging, and Ablation of Tumor-Associated Macrophages by Theranostic Mannose-AIEgen Conjugates.

Tumor-associated macrophages (TAMs) that exist in tumor microenvironment promote tumor progression and have been suggested as a promising therapeutic target for cancer therapy in preclinical studies. Development of theranostic systems capable of specific targeting, imaging, and ablation of TAMs will offer clinical benefits. Here we constructed a theranostic probe, namely, TPE-Man, by attaching mannose moieties to a red-emissive and AIE (aggregation-induced emission)-active photosensitizer. TPE-Man can specifically recognize a mannose receptor that is overexpressed on TAMs by the sugar-receptor interaction and enables fluorescent visualization of the mannose-receptor-positive TAMs in high contrast. The histologic study of mouse tumor sections further verifies TPE-Man's excellent targeting specificity being comparable with the commercial mannose-receptor antibody. TAMs can be effectively eradicated upon exposure to white light irradiation via a photodynamic therapy effect. To our knowledge, this is the first small molecular theranostic probe for TAMs that revealed combined advantages of low cost, high targeting specificity, fluorescent light-up imaging, and efficient photodynamic ablation.

Adaptive homeostasis of the vitamin D-vitamin D nuclear receptor axis in 8-methoxypsoralen-induced hepatotoxicity.

8-methoxypsoralen (8-MOP) with ultraviolet A radiation therapy (PUVA) is the standard therapy for patients with psoriasis, despite the reported potential risks of 8-MOP-induced cholestatic liver injury in both humans and animals. Usually, patients with chronic cholestasis exhibit lower serum 25-hydroxy vitamin D (25(OH)D) levels. But those patients receiving PUVA for psoriasis showed an increase in serum 25(OH)D levels, probably highlighting that the vitamin D-vitamin D nuclear receptor (VD-VDR) axis play a protective role in 8-MOP-induced hepatotoxicity. The present study confirmed 8-MOP could increase serum 25(OH)D levels in conventional lighting and diet (CLD) and vitamin D deficient (VDD) Sprague-Dawley rats. Potential liver risks were also found in CLD and VDD rats after 8-MOP treatment. We proved that 8-MOP could be a potent ligand for VDR using molecular docking and luciferase report assay. Effect of 8-MOP on VDR subcellular distribution was determined using human liver cell line L02. We found 8-MOP could increase VDR protein expression in the nuclear and cytosol extracts and also total cell extracts in L02. siRNAs for VDR were used to determine the role of VDR in protecting 8-MOP-induced cholestasis and potential cellular mechanisms. The results showed 8-MOP could affect the CYP7A1, SHP and MRP3 expression via VDR, and such effects could be reversed by knockdown of VDR expression, suggesting a vital role of VDR involved in 8-MOP-regulated bile acid synthesis and transportation. In conclusion, these results revealed activation of VD-VDR axis may play a beneficial role in 8-MOP-mediated regulation of bile acid synthesis and transportation.

Computational Investigation of Drug Phototoxicity: Photosafety Assessment, Photo-Toxophore Identification, and Machine Learning.

One of the most appreciated capabilities of computational toxicology is to support the design of pharmaceuticals with reduced toxicological hazard. To this end, we have strengthened our drug photosafety assessments by applying novel computer models for the anticipation of in vitro phototoxicity and human photosensitization. These models are typically used in pharmaceutical discovery projects as part of the compound toxicity assessments and compound optimization methods. To ensure good data quality and aiming at models with global applicability we separately compiled and curated highly chemically diverse data sets from 3T3 NRU phototoxicity reports (450 compounds) and clinical photosensitization alerts (1419 compounds) which are provided as supplements. The latter data gives rise to a comprehensive list of explanatory fragments for visual guidance, termed phototoxophores, by application of a Bayesian statistics approach. To extend beyond the domain of well sampled fragments we applied machine learning techniques based on explanatory descriptors such as pharmacophoric fingerprints or, more important, accurate electronic energy descriptors. Electronic descriptors were extracted from quantum chemical computations at the density functional theory (DFT) level. Accurate UV/vis spectral absorption descriptors and pharmacophoric fingerprints turned out to be necessary for predictive computer models, which were both derived from Deep Neural Networks but also the simpler Random Decision Forests approach. Model accuracies of 83-85% could typically be reached for diverse test data sets and other company in-house data, while model sensitivity (the capability of correctly detecting toxicants) was even better, reaching 86%-90%. Importantly, a computer model-triggered response-map allowed for graphical/chemical interpretability also in the case of previously unknown phototoxophores. The photosafety models described here are currently applied in a prospective manner for the hazard identification, prioritization, and optimization of newly designed molecules.

Comparative evaluation of the hepatotoxicity, phototoxicity and photosensitizing potential of dronedarone hydrochloride and its cyclodextrin-based inclusion complexes.

In this study, the hepatotoxicity, phototoxicity and photosensitizing potential of free dronedarone (DRO) and its inclusion complexes with ß-cyclodextrin (ß-CD) and 2-hydroxypropyl-ß-cyclodextrin (HP-ß-CD), prepared by different methods, were investigated by using in vitro cell-based approaches. The results of the 3T3 NRU phototoxicity assay showed that free DRO and the CD-based inclusion complexes did not present any substantial phototoxic potential. The photosensitizing potential was assessed by using THP-1 cells and IL-8 as a biomarker, and the experimental data confirmed that both the free drug and the inclusion complexes are likely to cause skin photosensitization, as they were able to induce IL-8 release after irradiation. Nevertheless, the inclusion complexes obtained by kneading followed by spray-drying induced a lower IL-8 release and also presented a smaller stimulation index in comparison with free DRO, suggesting a reduction in the photosensitizing potential. Finally, the free drug and inclusion complexes were also tested for hepatotoxicity using HepG2 cells. Even though lower IC50 values were found for the inclusion complexes prepared by kneading followed by spray-drying, there was no significant difference, indicating that the complexation of dronedarone did not induce hepatotoxicity. Overall, the obtained data confirmed that the inclusion complexes prepared by kneading followed by spray-drying, especially those based on HP-ß-CD, appeared to be the most promising formulations and, therefore, could be encouragingly explored in the development of novel pharmaceutical dosage forms containing DRO, presumably with reduced side effects and improved safety profile.

Screening of two-photon activated photodynamic therapy sensitizers using a 3D osteosarcoma model.

Photodynamic therapy (PDT) involves a photosensitizing agent activated with light to induce cell death. Two-photon excited PDT (TPE-PDT) offers numerous benefits compared to traditional one-photon induced PDT, including an increased penetration depth and precision. However, the in vitro profiling and comparison of two-photon photosensitizers (PS) are still troublesome. Herein, we report the development of an in vitro screening platform of TPE-PS using a 3D osteosarcoma cell culture. The platform was tested using three different two-photon (2P) active compounds - a 2P sensitizer P2CK, a fluorescent dye Eosin Y, and a porphyrin derivative (TPP). Their 2P absorption cross-sections (σ2PA) were characterised using a fully automated z-scan setup. TPP exhibited a remarkably high σ2PA at 720 nm (8865 GM) and P2CK presented a high absorption at 850 nm (405 GM), while Eosin Y had the lowest 2P absorption at the studied wavelengths (<100 GM). The cellular uptake of PS visualized using confocal laser scanning microscopy showed that both TPP and P2CK were internalized by the cells, while Eosin Y stayed mainly in the surrounding media. The efficiency of the former two TPE-PS was quantified using the PrestoBlue metabolic assay, showing a significant reduction in cell viability after two-photon irradiation. The possibility of damage localization was demonstrated using a co-culture of adipose derived stem cells together with osteosarcoma spheroids showing no signs of damage to the surrounding healthy cells after TPE-PDT.

A molecular hybrid producing simultaneously singlet oxygen and nitric oxide by single photon excitation with green light.

Combination of photosensitizers (PS) for photodynamic therapy with NO photodonors (NOPD) is opening intriguing horizons towards new and still underexplored multimodal anticancer and antibacterial treatments not based on "conventional" drugs and entirely controlled by light stimuli. In this contribution, we report an intriguing molecular hybrid based on a BODIPY light-harvesting antenna that acts simultaneously as PS and NOPD upon single photon excitation with the highly biocompatible green light. The presented hybrid offers a combination of superior advantages with respect to the other rare cases reported to date, meeting most of the key criteria for both PSs and NOPDs in the same molecular entity such as: (i) capability to generate 1O2 and NO with single photon excitation of biocompatible visible light, (ii) excellent 1O2 quantum yield and NO quantum efficiency, (iii) photogeneration of NO independent from the presence of oxygen, (iv) large light harvesting properties in the green region. Furthermore, this compound together with its stable photoproduct, is well tolerated by both normal and cancer cells in the dark and exhibits bimodal photomortality of cancer cells under green light excitation due to the combined action of the cytotoxic 1O2 and NO.

Polylysine modified conjugated polymer nanoparticles loaded with the singlet oxygen probe 1,3-diphenylisobenzofuran and the photosensitizer indocyanine green for use in fluorometric sensing and in photodynamic therapy.

Conjugated polymer hybrid nanoparticles (NPs) loaded with both indocyanine green (ICG) and 1,3-diphenylisobenzofuran (DPBF) are described. The NPs are dually functional in that ICG acts as the photosensitizer, and DPBF as a probe for singlet oxygen (1O2 probe). The nanoparticle core consists of the energy donating host poly(9,9-dioctylfluorenyl-2,7-diyl)-co-(2,5-p-xylene) (PFP). The polymer is doped with the energy acceptor DPBF. Ratiometric fluorometric detection of singlet oxygen is accomplished by measurement of fluorescence at wavelengths of 415 and 458 nm. In addition, the shell of the positively charged polymeric nanoparticles was modified, via electrostatic interaction, with negatively charged PDT drugs ICG. The integrated nanoparticles of type ICG-DPBF-PFP display effective photodynamic performance under 808-nm laser irradiation. The 1O2 sensing behaviors of samples are evaluated based on the ratiometric fluorescent responses produced by DPBF and PFP. 1O2 can be fluorimetically sensed with a detection limit of 28 µM. The multifunctional nanoprobes exhibit effortless cellular uptake, superior photodynamic activity and a rapid ratiometric response to 1O2. Graphical abstractSchematic of a dual-functional nanoplatform for photodynamic therapy (PDT) and singlet oxygen (1O2) feedback. It offers a new strategy for self-monitoring photodynamic ablation. FRET: fluorescence resonance energy transfer. Indocyanine green is attached in the shell of nanoparticles, and 1,3-diphenylisobenzofuran is doped into the energy donating host conjugated polymer.

Cryodesiccation-driven crystallization preparation approach for zinc(II)-phthalocyanine nanodots in cancer photodynamic therapy and photoacoustic imaging.

Multifunctional nanodots represent an emerging platform for overcoming the delivery challenges of poorly water-soluble drugs for use in the diagnosis and treatment of cancer. The authors describe the preparation of nanocrystallites composed of the water-insoluble photosensitizer zinc(II)-phthalocyanine in the form of nanodots by applying a cryodesiccation-driven crystallization approach. Modification of the surface of the nanodots with Pluronic F127 and folic acid endows them with excellent water solubility and stealth properties in blood. Under near-infrared (NIR) photoexcitation at 808 nm, the nanodots are shown to produce singlet oxygen, which is widely used in photodynamic therapy of cancer. The nanodots exhibit strong NIR absorbance at 808 nm and can be used as a non-toxic contrast agent for photoacoustic imaging of tissue. Graphical abstract Schematic presentation of the preparation of ZnPcNDs by droplet-confined/cryodesiccation-driven crystallization.

Engineering of Electrochromic Materials as Activatable Probes for Molecular Imaging and Photodynamic Therapy.

Electrochromic materials (EMs) are widely used color-switchable materials, but their applications as stimuli-responsive biomaterials to monitor and control biological processes remain unexplored. This study reports the engineering of an organic π-electron structure-based EM (dicationic 1,1,4,4-tetraarylbutadiene, 12+) as a unique hydrogen sulfide (H2S)-responsive chromophore amenable to build H2S-activatable fluorescent probes (12+-semiconducting polymer nanoparticles, 12+-SNPs) for in vivo H2S detection. We demonstrate that EM 12+, with a strong absorption (500-850 nm), efficiently quenches the fluorescence (580, 700, or 830 nm) of different fluorophores within 12+-SNPs, while the selective conversion into colorless diene 2 via H2S-mediated two-electron reduction significantly recovers fluorescence, allowing for non-invasive imaging of hepatic and tumor H2S in mice in real time. Strikingly, EM 12+ is further applied to design a near-infrared photosensitizer with tumor-targeting and H2S-activatable ability for effective photodynamic therapy (PDT) of H2S-related tumors in mice. This study demonstrates promise for applying EMs to build activatable probes for molecular imaging of H2S and selective PDT of tumors, which may lead to the development of new EMs capable of detecting and regulating essential biological processes in vivo.

Glycomimetic-Conjugated Photosensitizer for Specific Pseudomonas aeruginosa Recognition and Targeted Photodynamic Therapy.

Due to the rapid development of bacterial resistance, there is an urgent need to explore new antibacterial agents to substitute for traditional antibiotic therapy. Photodynamic therapy has been identified as a promising bactericidal method to conquer antibiotic-resistant pathogens. To solve the problem of photosensitizer damage to normal tissues in vivo, we developed a boron-dipyrrolemethene (BODIPY)-based glycosylated photosensitizer for ablating Pseudomonas aeruginosa ( P. aeruginosa). This glycosylated photosensitizer exhibited good water solubility and generated 1O2 rapidly in an aqueous solution under light exposure. The photosensitizer did not cause detectable toxicity to human cells in the dark. Importantly, the photosensitizer was able to selectively attach to P. aeruginosa over normal cells, thus resulting in effective pathogen ablation by reactive oxygen species. Moreover, the photosensitizer inhibited over 90% of the biofilm formation produced by P. aeruginosa. The results indicate that the design of the macromolecular photosensitizer-induced bacterial death and inhibited biofilm formation provide a novel strategy for overcoming bacterial infection.

Gaining Access to Bacteria through (Reversible) Control of Lipophilicity.

The development of antimicrobial photodynamic therapy (aPDT) is highly dependent on the development of suitable photosensitizers (PSs); ideally, affinity of a PS towards bacterial cells should be much higher than that towards mammalian cells. A cationic charge on a PS may lead to its selective binding to bacteria mediated through electrostatic interaction; however, the photodynamic outcome is highly dependent on the lipophilicity of the PS. Herein, we report the aPDT effect of silicon(IV) phthalocyanine derivatives bearing four positive charges and methyl, phenyl, or naphthyl substituents at the periphery of the macrocycle. We show that through modulation of lipophilicity, it is possible to find a therapeutic window in which bacteria, but not mammalian cells, are effectively killed. The photobiological activity of these PSs was significantly lower when they were deployed as host-guest complexes with cucurbit[7]uril (CB[7]). CB[7] blocks the hydrophobic part of the PS and reduces its lipophilicity, indicating that a hydrophobic interaction with the outer membrane of bacterial cells is essential for aPDT activity. The efficacies of the obtained PSs have been evaluated by using different uropathogenic E. coli isolates and human kidney epithelial carcinoma cells.

A graphene quantum dot-based multifunctional two-photon nanoprobe for the detection and imaging of intracellular glutathione and enhanced photodynamic therapy.

A multifunctional nanosystem, which integrates biosensing, bioimaging, and therapeutic functions into a single nanoprobe, is of great significance for biosensing and biomedicine. Near-infrared (NIR) graphene quantum dots (GQDs) have emerged as an attractive bioimaging and therapy tool for exploring biological events because they can provide deep imaging penetration and low fluorescence background and produce 1O2 for PDT. Here, we reported a GQD-based multifunctional two-photon nanoprobe for intracellular tumor-related glutathione (GSH) detection and enhanced photodynamic therapy by reducing GSH levels in cancer cells. By taking the excellent quenching property of MnO2 nanosheets and the reduction ability of GSH, a GQD@MnO2 nanoprobe was developed through adsorption of MnO2 nanosheets onto the surface of GQDs for sensing intracellular tumor-related GSH. The nanoprobe shows a highly sensitive response to GSH in aqueous solutions with a detection limit of 83 nM. It also exhibits a high selectivity toward GSH relative to other biomolecules and electrolytes. In addition, once endocytosed, the MnO2 nanosheets are reduced by intracellular GSH, simultaneously releasing GQDs and decreasing the level of GSH for highly efficient PDT.