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Pigment Cell & Melanoma Research May 2024Melanin, particularly eumelanin, is commonly viewed as an efficient antioxidant and photoprotective pigment. Nonetheless, the ability of melanin to photogenerate...
Melanin, particularly eumelanin, is commonly viewed as an efficient antioxidant and photoprotective pigment. Nonetheless, the ability of melanin to photogenerate reactive oxygen species and sensitize the formation of cyclobutane pyrimidine dimers may contribute to melanin-dependent phototoxicity. The phototoxic potential of melanin depends on a variety of factors, including molecular composition, redox state, and degree of aggregation. Using complementary spectroscopic and analytical methods we analyzed the physicochemical properties of Dopa-melanin, a synthetic model of eumelanin, subjected to oxidative degradation induced by aerobic photolysis or exposure to 0.1 M hydrogen peroxide. Both modes of oxidative degradation were accompanied by dose-dependent bleaching of melanin and irreversible modifications of its paramagnetic, ion- and electron-exchange and antioxidant properties. Bleached melanin exhibited enhanced efficiency to photogenerate singlet oxygen in both UVA and short-wavelength visible light. Although chemical changes of melanin subunits, including a relative increase of DHICA content and disruption of melanin polymer induced by oxidative degradation were considered, these two mechanisms may not be sufficient for a satisfactory explanation of the elevated photosensitizing ability of the bleached eumelanin. This study points out possible adverse changes in the photoprotective and antioxidant properties of eumelanin that could occur in pigmented tissues after exposure to high doses of intense solar radiation.
PubMed: 38803190
DOI: 10.1111/pcmr.13176 -
Nature Biotechnology May 2024Long-term observation of subcellular dynamics in living organisms is limited by background fluorescence originating from tissue scattering or dense labeling. Existing...
Long-term observation of subcellular dynamics in living organisms is limited by background fluorescence originating from tissue scattering or dense labeling. Existing confocal approaches face an inevitable tradeoff among parallelization, resolution and phototoxicity. Here we present confocal scanning light-field microscopy (csLFM), which integrates axially elongated line-confocal illumination with the rolling shutter in scanning light-field microscopy (sLFM). csLFM enables high-fidelity, high-speed, three-dimensional (3D) imaging at near-diffraction-limit resolution with both optical sectioning and low phototoxicity. By simultaneous 3D excitation and detection, the excitation intensity can be reduced below 1 mW mm, with 15-fold higher signal-to-background ratio over sLFM. We imaged subcellular dynamics over 25,000 timeframes in optically challenging environments in different species, such as migrasome delivery in mouse spleen, retractosome generation in mouse liver and 3D voltage imaging in Drosophila. Moreover, csLFM facilitates high-fidelity, large-scale neural recording with reduced crosstalk, leading to high orientation selectivity to visual stimuli, similar to two-photon microscopy, which aids understanding of neural coding mechanisms.
PubMed: 38802562
DOI: 10.1038/s41587-024-02249-5 -
Micromachines May 2024In recent years, diseases such as age-related macular degeneration and retinal pigment degeneration caused by excessive exposure to short-wavelength visible light have...
In recent years, diseases such as age-related macular degeneration and retinal pigment degeneration caused by excessive exposure to short-wavelength visible light have become significant concerns. With the aim of quantitatively evaluating the toxicity of short-wavelength light, proliferating cell nuclear antigen (PCNA) accumulation at the irradiation site was investigated using live cell imaging techniques to irradiate individual living cells with short-wavelength laser light. By examining the dependency of PCNA accumulation on the irradiation site within the cells and their cell cycle, it was observed that PCNA accumulation occurred only when the cell nucleus of cells in the S phase of the cell cycle was irradiated. We investigated the accumulation of PCNA at the laser irradiation site using laser light at wavelengths of 405 nm and 375 nm, with intensities ranging from 0.5 μW to 9.0 μW. The results confirmed an increase in PCNA accumulation with increasing intensity, and a higher accumulation was observed with laser light irradiation at a wavelength of 375 nm compared to 405 nm. By comparing the PCNA accumulation and 24 h cell viability, we demonstrated the feasibility of quantitatively assessing laser light toxicity through the measurement of PCNA accumulation.
PubMed: 38793219
DOI: 10.3390/mi15050646 -
Journal of Medicinal Chemistry Jun 2024Molecular hybridization is a well-established strategy for developing new drugs. In the pursuit of promising photosensitizers (PSs) with enhanced photodynamic therapy...
Molecular hybridization is a well-established strategy for developing new drugs. In the pursuit of promising photosensitizers (PSs) with enhanced photodynamic therapy (PDT) efficiency, a series of novel 5-fluorouracil (5FU) gallium corrole conjugates () were designed and synthesized by hybridizing a chemotherapeutic drug and PSs. Their photodynamic antitumor activity was also evaluated. The most active complex () possesses a low IC value of 0.185 μM and a phototoxic index of 541 against HepG2 cells. Additionally, the 5FU-gallium corrole conjugate () exhibited a synergistic increase in cytotoxicity under irradiation. Excitedly, treatment of HepG2 tumor-bearing mice with under irradiation could completely ablate tumors without harming normal tissues. -mediated PDT could disrupt mitochondrial function, cause cell cycle arrest in the sub-G1 phase, and activate the cell apoptosis pathway by upregulating the cleaved PARP expression and the Bax/Bcl-2 ratios. This work provides a useful strategy for the design of new corrole-based chemo-photodynamic therapy drugs.
Topics: Photochemotherapy; Fluorouracil; Humans; Gallium; Animals; Porphyrins; Photosensitizing Agents; Mice; Apoptosis; Hep G2 Cells; Antineoplastic Agents; Mice, Inbred BALB C; Mice, Nude
PubMed: 38781403
DOI: 10.1021/acs.jmedchem.4c00249 -
European Journal of Medicinal Chemistry Jul 2024Photodynamic therapy (PDT), an emerging tumor therapeutic strategy has received tremendous attention. Enslaved by the high dependence of oxygen, Type-II photosensitizers...
Photodynamic therapy (PDT), an emerging tumor therapeutic strategy has received tremendous attention. Enslaved by the high dependence of oxygen, Type-II photosensitizers (PSs) mediated PDT is restricted by the hypoxic environment of tumors. By transferring electrons to water or other substrates instead of oxygen, Type-I PSs hold the promise of achieving an ideal therapeutic effect under hypoxic conditions. In this study, three twisted-backbone PSs (CBz-TQs-1, CBz-TQs-2 and CBz-TQs-3) are synthesized and studied. Owing to different substituent effects, the ROS generation mechanism transfers from pure Type-II of their prototype PSs (TQs-1, TQs-2 and TQs-3) to mixed Type-I/II of CBz-TQs-1 and CBz-TQs-2 to pure Type-I of CBz-TQs-3. Moreover, CBz-TQs-3 exhibits an ultra-high ROS quantum yield (∼1.0). The in vitro and in vivo PDT effects of water-dissolvable nanoparticles (NPs) of CBz-TQs-3 are investigated. The results show that the phototoxicity of CBz-TQs-3 is not affected by hypoxic environments. In addition, a remarkable tumor ablation can be found after CBz-TQs-3 NPs mediated PDT on Balb/c mice with xenograft tumors. It proves that a twisted backbone strategy is beneficial for designing pure Type-I PSs with high-efficient hypoxic PDT.
Topics: Photosensitizing Agents; Photochemotherapy; Animals; Humans; Mice; Drug Design; Mice, Inbred BALB C; Molecular Structure; Reactive Oxygen Species; Antineoplastic Agents; Drug Screening Assays, Antitumor; Structure-Activity Relationship; Dose-Response Relationship, Drug; Cell Line, Tumor; Cell Proliferation; Cell Survival; Female; Nanoparticles
PubMed: 38762917
DOI: 10.1016/j.ejmech.2024.116503 -
Advanced Materials (Deerfield Beach,... May 2024The emergence of multidrug resistant (MDR) pathogens and the scarcity of new potent antibiotics and antifungals are one of the biggest threats to human health....
The emergence of multidrug resistant (MDR) pathogens and the scarcity of new potent antibiotics and antifungals are one of the biggest threats to human health. Antimicrobial photodynamic therapy (aPDT) combines light and photosensitizers to kill drug-resistant pathogens; however, there are limited materials that can effectively ablate different classes of infective pathogens. In the present work, a new class of benzodiazole-paired materials is designed as highly potent PDT agents with broad-spectrum antimicrobial activity upon illumination with nontoxic light. The results mechanistically demonstrate that the energy transfer and electron transfer between nonphotosensitive and photosensitive benzodiazole moieties embedded within pathogen-binding peptide sequences result in increased singlet oxygen generation and enhanced phototoxicity. Chemical optimization renders PEP3 as a novel PDT agent with remarkable activity against MDR bacteria and fungi as well as pathogens at different stages of development (e.g., biofilms, spores, and fungal hyphae), which also prove effective in an ex vivo porcine model of microbial keratitis. The chemical modularity of this strategy and its general compatibility with peptide-based targeting agents will accelerate the design of highly photosensitive materials for antimicrobial PDT.
PubMed: 38762778
DOI: 10.1002/adma.202404107 -
Journal of Colloid and Interface Science Sep 2024The clinical translation of photosensitizers based on ruthenium(II) polypyridyl complexes (RPCs) in photodynamic therapy of cancer faces several challenges. To address...
The clinical translation of photosensitizers based on ruthenium(II) polypyridyl complexes (RPCs) in photodynamic therapy of cancer faces several challenges. To address these limitations, we conducted an investigation to assess the potential of a cubosome formulation stabilized in water against coalescence utilizing a polyphosphoester analog of Pluronic F127 as a stabilizer and loaded with newly synthesized RPC-based photosensitizer [Ru(dppn)(bpy-morph)](PF) (bpy-morph = 2,2'-bipyridine-4,4'-diylbis(morpholinomethanone)), PS-Ru. The photophysical characterization of PS-Ru revealed its robust capacity to induce the formation of singlet oxygen (O). Furthermore, the physicochemical analysis of the PS-Ru-loaded cubosomes dispersion demonstrated that the encapsulation of the photosensitizer within the nanoparticles did not disrupt the three-dimensional arrangement of the lipid bilayer. The biological tests showed that PS-Ru-loaded cubosomes exhibited significant phototoxic activity when exposed to the light source, in stark contrast to empty cubosomes and to the same formulation without irradiation. This promising outcome suggests the potential of the formulation in overcoming the drawbacks associated with the clinical use of RPCs in photodynamic therapy for anticancer treatments.
Topics: Photochemotherapy; Photosensitizing Agents; Lung Neoplasms; Humans; Ruthenium; Coordination Complexes; Adenocarcinoma of Lung; Antineoplastic Agents; Particle Size; Singlet Oxygen; Nanoparticles; Cell Survival; Poloxamer; Drug Screening Assays, Antitumor; Surface Properties; A549 Cells
PubMed: 38761576
DOI: 10.1016/j.jcis.2024.05.088 -
Drug Delivery and Translational Research May 2024Photodynamic Therapy (PDT) is a promising paradigm for treating cancer, especially superficial cancers, including skin and oral cancers. However, the effectiveness of...
Photodynamic Therapy (PDT) is a promising paradigm for treating cancer, especially superficial cancers, including skin and oral cancers. However, the effectiveness of PDT is hindered by the hydrophobicity of photosensitizers. Here, chlorin e6 (Ce6), a hydrophobic photosensitizer, was loaded into pluronic F127 micelles to enhance solubility and improve tumor-specific targeting efficiency. The resulting Ce6@F127 Ms demonstrated a significant increase in solubility and singlet oxygen generation (SOG) efficiency in aqueous media compared to free Ce6. The confocal imaging and fluorescence-activated cell sorting (FACS) analysis confirmed the enhanced internalization rate of Ce6@F127 Ms in murine melanoma cell lines (B16F10) and human oral carcinoma cell lines (FaDu). Upon laser irradiation (666 nm), the cellular phototoxicity of Ce6@F127 Ms against B16F10 and FaDu was approximately three times higher than the free Ce6 treatment. The in vivo therapeutic investigations conducted on a murine model of skin cancer demonstrated the ability of Ce6@F127 Ms, when combined with laser treatment, to penetrate solid tumors effectively, which resulted in a significant reduction in tumor volume compared to free Ce6. Further, the Ce6@F127 Ms demonstrated upregulation of TUNEL-positive cells, downregulation of proliferation markers in tumor tissues, and prevention of lung metastasis with insignificant levels of proliferating cells and collagenase, as validated through immunohistochemistry. Subsequent analysis of serum and blood components affirmed the safety and efficacy of Ce6@F127 Ms in mice. Consequently, the developed Ce6@F127 Ms exhibits significant potential for concurrently treating solid tumors and preventing metastasis. The photodynamic formulation holds great clinical translation potential for treating superficial tumors.
PubMed: 38755500
DOI: 10.1007/s13346-024-01619-5 -
ACS Applied Materials & Interfaces May 2024The practical application of photodynamic therapy (PDT) demands targeted and activatable photosensitizers to mitigate off-target phototoxicity common in "always on"...
Hydrogen Sulfide-Induced Activatable Photodynamic Therapy Adjunct to Disruption of Subcellular Glycolysis in Cancer Cells by a Fluorescence-SERS Bimodal Iridium Metal-Organic Hybrid.
The practical application of photodynamic therapy (PDT) demands targeted and activatable photosensitizers to mitigate off-target phototoxicity common in "always on" photosensitizers during light exposure. Herein, a cyclometalated iridium complex-based activatable photodynamic molecular hybrid, Cy-Ir-7-nitrobenzofurazan (NBD), is demonstrated as a biomedicine for molecular precision. This design integrates a hydrogen sulfide (HS)-responsive NBD unit with a hydroxy-appended iridium complex, Cy-Ir-OH. In normal physiological conditions, the electron-rich Ir metal center exerts electron transfer to the NBD unit, quenches the excited state dynamics, and establishes a PDT-off state. Upon exposure to HS, Cy-Ir-NBD activates into the potent photosensitizer Cy-Ir-OH through nucleophilic substitution. This mechanism ensures exceptional specificity, enabling targeted phototherapy in HS-rich cancer cells. Additionally, we observed that Cy-Ir-NBD-induced HS depletion disrupts S-sulfhydration of the glyceraldehyde-3-phosphate dehydrogenase enzyme, impairing glycolysis and ATP production in the cellular milieu. This sequential therapeutic process of Cy-Ir-NBD is governed by the positively charged central iridium ion that ensures mitochondria-mediated apoptosis in cancer cells. Dual-modality SERS and fluorescence imaging validate apoptotic events, highlighting Cy-Ir-NBD as an advanced theranostic molecular entity for activatable PDT. Finally, as a proof of concept, clinical assessment is evaluated with the blood samples of breast cancer patients and healthy volunteers, based on their HS overexpression capability through SERS and fluorescence, revealing Cy-Ir-NBD to be a promising predictor for PDT activation in advanced cancer phototherapy.
Topics: Humans; Photochemotherapy; Iridium; Hydrogen Sulfide; Photosensitizing Agents; Glycolysis; Neoplasms; Cell Line, Tumor; Fluorescence
PubMed: 38747624
DOI: 10.1021/acsami.4c02761 -
Angewandte Chemie (International Ed. in... May 2024Electrochemiluminescence (ECL) is rapidly evolving from an analytical method into an optical microscopy. The orthogonality of the electrochemical trigger and the optical... (Review)
Review
Electrochemiluminescence (ECL) is rapidly evolving from an analytical method into an optical microscopy. The orthogonality of the electrochemical trigger and the optical readout distinguishes it from classic microscopy and electrochemical techniques, owing to its near-zero background, remarkable sensitivity, and absence of photobleaching and phototoxicity. In this minireview, we summarize the recent advances in ECL imaging technology, emphasizing original configurations which enable the imaging of biological entities and the improvement of the analytical properties by increasing the complexity and multiplexing of bioassays. Additionally, mapping the (electro)chemical reactivity in space provides valuable information on nanomaterials and facilitates deciphering ECL mechanisms for improving their performances in diagnostics and (electro)catalysis. Finally, we highlight the recent achievements in imaging at the ultimate limits of single molecules, single photons or single chemical reactions, and the current challenges to translate the ECL imaging advances to other fields such as material science, catalysis and biology.
PubMed: 38742673
DOI: 10.1002/anie.202407588