Extension of nature's NIR-I chromophore into the NIR-II region.

The development of chromophores that absorb in the near-infrared (NIR) region beyond 1000 nm underpins numerous applications in medical and energy sciences, yet also presents substantial challenges to molecular design and chemical synthesis. Here, the core bacteriochlorin chromophore of nature's NIR absorbers, bacteriochlorophylls, has been adapted and tailored by annulation in an effort to achieve absorption in the NIR-II region. The resulting bacteriochlorin, Phen2,1-BC, contains two annulated naphthalene groups spanning meso,ß-positions of the bacteriochlorin and the 1,2-positions of the naphthalene. Phen2,1-BC was prepared via a new synthetic route. Phen2,1-BC is an isomer of previously examined Phen-BC, which differs only in attachment via the 1,8-positions of the naphthalene. Despite identical π-systems, the two bacteriochlorins have distinct spectroscopic and photophysical features. Phen-BC has long-wavelength absorption maximum (912 nm), oscillator strength (1.0), and S1 excited-state lifetime (150 ps) much different than Phen2,1-BC (1292 nm, 0.23, and 0.4 ps, respectively). These two molecules and an analogue with intermediate characteristics bearing annulated phenyl rings have unexpected properties relative to those of non-annulated counterparts. Understanding the distinctions requires extending concepts beyond the four-orbital-model description of tetrapyrrole spectroscopic features. In particular, a reduction in symmetry resulting from annulation results in electronic mixing of x- and y-polarized transitions/states, as well as vibronic coupling that together reduce oscillator strength of the long-wavelength absorption manifold and shorten the S1 excited-state lifetime. Collectively, the results suggest a heuristic for the molecular design of tetrapyrrole chromophores for deep penetration into the relatively unutilized NIR-II region.

A TME-enlightened protein-binding photodynamic nanoinhibitor for highly effective oncology treatment.

The efficiency of photodynamic therapy (PDT) is greatly dependent on intrinsic features of photosensitizers (PSs), but most PSs suffer from narrow diffusion distances and short life span of singlet oxygen (1O2). Here, to conquer this issue, we propose a strategy for in situ formation of complexes between PSs and proteins to deactivate proteins, leading to highly effective PDT. The tetrafluorophenyl bacteriochlorin (FBC), a strong near-infrared absorbing photosensitizer, can tightly bind to intracellular proteins to form stable complexes, which breaks through the space-time constraints of PSs and proteins. The generated singlet oxygen directly causes the protein dysfunction, leading to high efficiency of PSs. To enable efficient delivery of PSs, a charge-conversional and redox-responsive block copolymer POEGMA-b-(PAEMA/DMMA-co-BMA) (PB) was designed to construct a protein-binding photodynamic nanoinhibitor (FBC@PB), which not only prolongs blood circulation and enhances cellular uptake but also releases FBC on demand in tumor microenvironment (TME). Meanwhile, PDT-induced destruction of cancer cells could produce tumor-associated antigens which were capable to trigger robust antitumor immune responses, facilitating the eradication of residual cancer cells. A series of experiments in vitro and in vivo demonstrated that this multifunctional nanoinhibitor provides a promising strategy to extend photodynamic immunotherapy.

Self-Amplified pH/ROS Dual-Responsive Co-Delivery Nano-System with Chemo-Photodynamic Combination Therapy in Hepatic Carcinoma Treatment.

Background: Chemo-photodynamic combination therapy has demonstrated significant potential in the treatment of cancer. Triptolide (TPL), a naturally derived anticancer agent, when combined with the photosensitizer Chlorin e6 (Ce6), has shown to provide enhanced anti-tumor benefits. However, the development of stimuli-responsive nanovehicles for the co-delivery of TPL and Ce6 could further enhance the efficacy of this combination therapy. Methods: In this study, we synthesized a pH/ROS dual-responsive mPEG-TK-PBAE copolymer, which contains a pH-sensitive PBAE moiety and a ROS-sensitive thioketal (TK) linkage. Through a self-assembly process, TPL and Ce6 were successfully co-loaded into mPEG-TK-PBAE nanoparticles, hereafter referred to as TPL/Ce6 NPs. We evaluated the pH- and ROS-sensitive drug release and particle size changes. Furthermore, we investigated both the in vitro suppression of cellular proliferation and induction of apoptosis in HepG2 cells, as well as the in vivo anti-tumor efficacy of TPL/Ce6 NPs in H22 xenograft nude mice. Results: The mPEG-TK-PBAE copolymer was synthesized through a one-pot Michael-addition reaction and successfully co-encapsulated both TPL and Ce6 by self-assembly. Upon exposure to acid pH values and high ROS levels, the payloads in TPL/Ce6 NPs were rapidly released. Notably, the abundant ROS generated by the released Ce6 under laser irradiation further accelerated the degradation of the nanosystem, thereby amplifying the tumor microenvironment-responsive drug release and enhancing anticancer efficacy. Consequently, TPL/Ce6 NPs significantly increased PDT-induced oxidative stress and augmented TPL-induced apoptosis in HepG2 cells, leading to synergistic anticancer effects in vitro. Moreover, administering TPL/Ce6 NPs (containing 0.3 mg/kg of TPL and 4 mg/kg of Ce6) seven times, accompanied by 650 nm laser irradiation, efficiently inhibited tumor growth in H22 tumor-bearing mice, while exhibiting lower systemic toxicity. Conclusion: Overall, we have developed a tumor microenvironment-responsive nanosystem for the co-delivery of TPL and Ce6, demonstrating amplified synergistic effects of chemo-photodynamic therapy (chemo-PDT) for hepatocellular carcinoma (HCC) treatment.

Porphyrins with combinations of 4-carboxyphenyl and 4-hydroxyphenyl substituents in meso-positions as anti-HIV-1 agents.

A series of 4-carboxyphenyl/4-hydroxyphenyl meso-substituted porphyrins were synthesized, purified, and characterized. The compounds exhibited anti-HIV-1 activities, in vitro, under both non-photodynamic (non-PDT) and photodynamic (PDT) conditions. Specifically, the porphyrins inhibited HIV-1 virus entry, with c-PB2(OH)2 and PB(OH)3 showing significant anti-HIV-1 activity. All of the porphyrins inhibited HIV-1 subtype B and C virus entry under PDT conditions. Our study demonstrated that the compounds bearing combinations of 4-carboxyphenyl/4-hydroxyphenyl moieties were not toxic even at higher concentrations, as compared to the reference porphyrins 5,10,15,20-tetra-(4-carboxyphenyl)porphyrin (TCPP) and 5,10,15,20-tetra-(4-hydroxyphenyl)porphyrin (THPP), under PDT conditions. This study underscores the promising potential of these compounds as HIV entry inhibitors in both non-PDT and PDT scenarios.

Efficient porphyrin integrated UiO-66 probes for ratiometric fluorescence sensing of antibiotic residues in milk.

Dual-emissive fluorescence probes were designed by integrating porphyrin into the frameworks of UiO-66 for ratiometric fluorescence sensing of amoxicillin (AMX). Porphyrin integrated UiO-66 showed dual emission in the blue and red region. AMX resulted in the quenching of blue fluorescence component, attributable to the charge neutralization and hydrogen bonds induced energy transfer. AMX was detected using (F438/F654) as output signals. Two linear relationships were observed (from 10 to 1000 nM and 1 to 100 µM), with a limit of detection of 27 nM. The porphyrin integrated UiO-66 probe was used to detect AMX in practical samples. This work widens the road for the development of dual/multiple emissive fluorescence sensors for analytical applications, providing materials and theoretical supporting for food, environmental, and human safety.

Porphyrin-based covalent organic framework as oxidase mimic for highly sensitive colorimetric detection of pesticides.

A covalent organic framework-based strategy was designed for label-free colorimetric detection of pesticides. Covalent organic framework-based nanoenzyme with excellent oxidase-like catalytic activity was synthesized. Unlike other artificial enzymes, porphyrin-based covalent organic framework (p-COF) as the oxidase mimic showed highly catalytic chromogenic activity and good affinity toward TMB without the presence of H2O2, which can be used as substitute for peroxidase mimics and H2O2 system in the colorimetric reaction. Based on the fact that the pesticide-aptamer complex can inhibit the oxidase activity of p-COF and reduced the absorbance at 650 nm in UV-Vis spectrum, a label-free and facile colorimetric detection of pesticides was designed and fabricated. Under the optimized conditions, the COF-based colorimetric probe for pesticide detection displayed high sensitivity and selectivity. Taking fipronil for example the limit of detection was 2.7 ng/mL and the linear range was 5 -500,000 ng/mL. The strategy was successfully applied to the detection of pesticides with good recovery , which was in accordance with that of HPLC-MS/MS. The COF-based colorimetric detection was free of complicated modification H2O2, which guaranteed the accuracy and reliability of measurements. The COF-based sensing strategy is a potential candidate for the sensitive detection of pesticides of interests.

The Hippo pathway terminal effector TAZ/WWTR1 mediates oxaliplatin sensitivity in p53 proficient colon cancer cells.

YAP and TAZ, the Hippo pathway terminal transcriptional activators, are frequently upregulated in cancers. In tumor cells, they have been mainly associated with increased tumorigenesis controlling different aspects from cell cycle regulation, stemness, or resistance to chemotherapies. In fewer cases, they have also been shown to oppose cancer progression, including by promoting cell death through the action of the p73/YAP transcriptional complex, in particular after chemotherapeutic drug exposure. Using HCT116 cells, we show here that oxaliplatin treatment led to core Hippo pathway down-regulation and nuclear accumulation of TAZ. We further show that TAZ was required for the increased sensitivity of HCT116 cells to oxaliplatin, an effect that appeared independent of p73, but which required the nuclear relocalization of TAZ. Accordingly, Verteporfin and CA3, two drugs affecting the activity of YAP and TAZ, showed antagonistic effects with oxaliplatin in co-treatments. Importantly, using several colorectal cell lines, we show that the sensitizing action of TAZ to oxaliplatin is dependent on the p53 status of the cells. Our results support thus an early action of TAZ to sensitize cells to oxaliplatin, consistent with a model in which nuclear TAZ in the context of DNA damage and p53 activity pushes cells towards apoptosis.

Multifaceted Applications of Luminescent Metalloporphyrin Derivatives: Fluorescence Turn-On Sensing of Nicotine and Antimicrobial Activity.

In this study, we designed and synthesized metalloporphyrin derivatives (with Ni and Zn) specifically intended for the fluorescence detection of nicotine in aqueous solutions. Our results showcased a notable selectivity for nicotine over other naturally occurring food toxins, exhibiting an exceptional sensitivity with a limit of detection as low as 7.2 nM. Through mechanistic investigations (1H NMR, FT-IR, etc.), we elucidated the binding mechanism, revealing the specific interaction between the pyridine ring of nicotine and the metal center, while the N atom pyrrolidine unit engaged in the hydrogen bonding with the side chain of the porphyrin ring. Notably, we observed that the nature of the metal center dictated the extent of interaction with nicotine; particularly, Zn-porphyrin demonstrated a superior response compared to Ni-porphyrin. Furthermore, we performed the quantitative estimation of nicotine in commercially available tobacco products. Additionally, we conducted the antibacterial (Staphylococcus aureus and Escherichia coli) and antifungal (Candida albicans) activities of the porphyrin derivatives.

Resonance Raman study of oxoiron(IV) porphyrin π-cation radical complex: Porphyrin ligand effect on ν(Fe=O) frequency.

Resonance Raman (rR) spectroscopy has been applied to study the nature of the iron-oxo (Fe=O) moiety of oxoiron(IV) porphyrin π-cation radical complex (CompI). While the axial ligand effect on the nature of the Fe=O moiety has been studied with rR spectroscopy, the porphyrin ligand effect has not been studied well. Here, we investigated the porphyrin ligand effect on the Fe=O moiety with rR spectroscopy. The porphyrin ligand effect was modulated by the electron-withdrawing effect of the porphyrin substituent at the meso-position. This study shows that the frequency of the Fe=O stretching band, ν(Fe=O), hardly change even when the electron-withdrawing effect of the porphyrin substituent changes. This result is further supported by theoretical calculation of CompI. The natural atomic charge analysis reveals that the oxo and axial ligands work to buffer the electron-withdrawing effect of the porphyrin substituent. The electron-withdrawing porphyrin substituent shifts an electron population from the ferryl iron to the porphyrin, but the decreased electron population on the ferryl iron is compensated by the shift of the electron population from the oxo ligand and the axial ligand. The shift of the electron population makes the Fe-axial ligand bond length short, but the Fe=O bond length unchanged, resulting in the invariable ν(Fe=O) frequency.

On the Possibility of Using 5-Aminolevulinic Acid in the Light-Induced Destruction of Microorganisms.

Antimicrobial photodynamic inactivation (aPDI) is a method that specifically kills target cells by combining a photosensitizer and irradiation with light at the appropriate wavelength. The natural amino acid, 5-aminolevulinic acid (5-ALA), is the precursor of endogenous porphyrins in the heme biosynthesis pathway. This review summarizes the recent progress in understanding the biosynthetic pathways and regulatory mechanisms of 5-ALA synthesis in biological hosts. The effectiveness of 5-ALA-aPDI in destroying various groups of pathogens (viruses, fungi, yeasts, parasites) was presented, but greater attention was focused on the antibacterial activity of this technique. Finally, the clinical applications of 5-ALA in therapies using 5-ALA and visible light (treatment of ulcers and disinfection of dental canals) were described.

Fluorescence lifetime imaging and phasor analysis of intracellular porphyrinic photosensitizers applied with different polymeric formulations.

The fluorescence lifetime of a porphyrinic photosensitizer (PS) is an important parameter to assess the aggregation state of the PS even in complex biological environments. Aggregation-induced quenching of the PS can significantly reduce the yield of singlet oxygen generation and thus its efficiency as a medical drug in photodynamic therapy (PDT) of diseased tissues. Hydrophobicity and the tendency to form aggregates pose challenges on the development of efficient PSs and often require carrier systems. A systematic study was performed to probe the impact of PS structure and encapsulation into polymeric carriers on the fluorescence lifetime in solution and in the intracellular environment. Five different porphyrinic PSs including chlorin e6 (Ce6) derivatives and tetrakis(m-hydroxyphenyl)-porphyrin and -chlorin were studied in free form and combined with polyvinylpyrrolidone (PVP) or micelles composed of triblock-copolymers or Cremophor. Following incubation of HeLa cells with these systems, fluorescence lifetime imaging combined with phasor analysis and image segmentation was applied to study the lifetime distribution in the intracellular surrounding. The data suggest that for free PSs, the structure-dependent cell uptake pathways determine their state and emission lifetimes. PS localization in the plasma membrane yielded mostly monomers with long fluorescence lifetimes whereas the endocytic pathway with subsequent lysosomal deposition adds a short-lived component for hydrophilic anionic PSs. Prolonged incubation times led to increasing contributions from short-lived components that derive from aggregates mainly localized in the cytoplasm. Encapsulation of PSs into polymeric carriers led to monomerization and mostly fluorescence emission decays with long fluorescence lifetimes in solution. However, the efficiency depended on the binding strength that was most pronounced for PVP. In the cellular environment, PVP was able to maintain monomeric long-lived species over prolonged incubation times. This was most pronounced for Ce6 derivatives with a logP value around 4.5. Micellar encapsulation led to faster release of the PSs resulting in multiple components with long and short fluorescence lifetimes. The hydrophilic hardly aggregating PS exhibited a mostly stable invariant lifetime distribution over time with both carriers. The presented data are expected to contribute to optimized PDT treatment protocols and improved PS-carrier design for preventing intracellular fluorescence quenching. In conclusion, amphiphilic and concurrent hydrophobic PSs with high membrane affinity as well as strong binding to the carrier have best prospects to maintain their photophysical properties in vivo and serve thus as efficient photodynamic diagnosis and PDT drugs.

Specific photodamage on HT-29 cancer cells leads to endolysosomal failure and autophagy blockage by cathepsin depletion.

Endolysosomes perform a wide range of cellular functions, including nutrient sensing, macromolecule digestion and recycling, as well as plasma membrane repair. Because of their high activity in cancerous cells, endolysosomes are attractive targets for the development of novel cancer treatments. Light-activated compounds termed photosensitizers (PS) can catalyze the oxidation of specific biomolecules and intracellular organelles. To selectively damage endosomes and lysosomes, HT-29 colorectal cancer cells were incubated with nanomolar concentrations of meso-tetraphenylporphine disulfonate (TPPS2a), an amphiphilic PS taken up via endocytosis and activated by green light (522 nm, 2.1 J.cm-1). Several cellular responses were characterized by a combination of immunofluorescence and immunoblotting assays. We showed that TPPS2a photosensitization blocked autophagic flux without extensive endolysosomal membrane rupture. Nevertheless, there was a severe functional failure of endolysosomes due to a decrease in CTSD (cathepsin D, 55%) and CTSB (cathepsin B, 52%) maturation. PSAP (prosaposin) processing (into saposins) was also considerably impaired, a fact that could be detrimental to glycosphingolipid homeostasis. Therefore, photosensitization of HT-29 cells previously incubated with a low concentration of TPPS2a promotes endolysosomal dysfunction, an effect that can be used to improve cancer therapies.

Synergistic photogeneration of nitric oxide and singlet oxygen by nanofiber membranes via blue and/or red-light irradiation: Strong antibacterial action.

New functionalities were added to biocompatible polycaprolactone nanofiber materials through the co-encapsulation of chlorin e6 trimethyl ester (Ce6) photogenerating singlet oxygen and absorbing light both in the blue and red regions, and using 4-(N-(aminopropyl)-3-(trifluoromethyl)-4-nitrobenzenamine)-7-nitrobenzofurazan, NO-photodonor (NOP), absorbing light in the blue region of visible light. Time-resolved and steady-state luminescence, as well as absorption spectroscopy, were used to monitor both photoactive compounds. The nanofiber material exhibited photogeneration of antibacterial species, specifically nitric oxide and singlet oxygen, upon visible light excitation. This process resulted in the efficient photodynamic inactivation of E. coli not only close to nanofiber material surfaces due to short-lived singlet oxygen, but even at longer distances due to diffusion of longer-lived nitric oxide. Interestingly, nitric oxide was also formed by processes involving photosensitization of Ce6 during irradiation by red light. This is promising for numerous applications, especially in the biomedical field, where strictly local photogeneration of NO and its therapeutic benefits can be applied using excitation in the "human body phototherapeutic window" (600-850 nm). Generally, due to the high permeability of red light, the photogeneration of NO can be achieved in any aqueous environment where direct excitation of NOP to its absorbance in the blue region is limited.

Evaluation and activity of new porphyrin-peptide cage-type conjugates for the photoinactivation of Mycobacterium abscessus.

Mycobacterium abscessus is increasingly recognized as an emerging opportunistic pathogen causing severe lung diseases and cutaneous infections. However, treatment of M. abscessus infections remains particularly challenging, largely due to intrinsic resistance to a wide panel of antimicrobial agents. New therapeutic alternatives are urgently needed. Herein, we show that, upon limited irradiation with a blue-light source, newly developed porphyrin-peptide cage-type photosensitizers exert a strong bactericidal activity against smooth and rough variants of M. abscessus in planktonic cultures and in biofilms, at low concentrations. Atomic force microscopy unraveled important morphological alterations that include a wrinkled and irregular bacterial surface. The potential of these compounds for a photo-therapeutic use to treat M. abscessus skin infections requires further evaluations.IMPORTANCEMycobacterium abscessus causes persistent infections and is extremely difficult to eradicate. Despite intensive chemotherapy, treatment success rates remain very low. Thus, given the unsatisfactory performances of the current regimens, more effective therapeutic alternatives are needed. In this study, we evaluated the activity of newly described porphyrin-peptide cage-type conjugates in the context of photodynamic therapy. We show that upon light irradiation, these compounds were highly bactericidal against M. abscessus in vitro, thus qualifying these compounds for future studies dedicated to photo-therapeutic applications against M. abscessus skin infections.

Targeted pH-Activated Peptide-Based Nanomaterials for Combined Photodynamic Therapy with Immunotherapy.

Photodynamic therapy (PDT) has demonstrated efficacy in eliminating local tumors, yet its effectiveness against metastasis is constrained. While immunotherapy has exhibited promise in a clinical context, its capacity to elicit significant systemic antitumor responses across diverse cancers is often limited by the insufficient activation of the host immune system. Consequently, the combination of PDT and immunotherapy has garnered considerable attention. In this study, we developed pH-responsive porphyrin-peptide nanosheets with tumor-targeting capabilities (PRGD) that were loaded with the IDO inhibitor NLG919 for a dual application involving PDT and immunotherapy (PRGD/NLG919). In vitro experiments revealed the heightened cellular uptake of PRGD/NLG919 nanosheets in tumor cells overexpressing αvß3 integrins. The pH-responsive PRGD/NLG919 nanosheets demonstrated remarkable singlet oxygen generation and photocytotoxicity in HeLa cells in an acidic tumor microenvironment. When treating HeLa cells with PRGD/NLG919 nanosheets followed by laser irradiation, a more robust adaptive immune response occurred, leading to a substantial proliferation of CD3+CD8+ T cells and CD3+CD4+ T cells compared to control groups. Our pH-responsive targeted PRGD/NLG919 nanosheets therefore represent a promising nanosystem for combination therapy, offering effective PDT and an enhanced host immune response.

Light-inducible nanodrug-mediated photodynamic and anti-apoptotic synergy for enhanced immunotherapy in triple-negative breast cancer.

Triple negative breast cancer (TNBC) exhibits limited responsiveness to immunotherapy owing to its immunosuppressive tumor microenvironment (TME). Here, a reactive oxygen species (ROS)-labile nanodrug encapsulating the photosensitizer Ce6 and Bcl-2 inhibitor ABT-737 was developed to provoke a robust immune response via the synergistic effect of photodynamic therapy (PDT) and the reversal of apoptosis resistance. Upon exposure to first-wave near-infrared laser irradiation, the generated ROS triggers PEG cleavage, facilitating the accumulation of the nanodrug at tumor region and endocytosis by tumor cells. Further irradiation leads to the substantial generation of cytotoxic ROS, initiating an immunogenic cell death (ICD) cascade, which prompts the maturation of dendritic cells (DCs) as well as the infiltration of T cells into the tumor site. Meanwhile, Bcl-2 inhibition counteracts apoptosis resistance, thereby amplifying PDT-induced ICD and bolstering antitumor immunity. As a result, the ROS-sensitive nanodrug demonstrates a potent inhibitory effect on tumor growth.

Impact of Fe3O4-porphyrin hybrid nanoparticles on wheat: Physiological and metabolic advance.

Iron-magnetic nanoparticles (Fe-NMPs) are widely used in environmental remediation, while porphyrin-based hybrid materials anchored to silica-coated Fe3O4-nanoparticles (Fe3O4-NPs) have been used for water disinfection purposes. To assess their safety on plants, especially concerning potential environmental release, it was investigated for the first time, the impact on plants of a silica-coated Fe3O4-NPs bearing a porphyrinic formulation (FORM) - FORM@NMP. Additionally, FORM alone and the magnetic nanoparticles without FORM anchored (NH2@NMP) were used for comparison. Wheat (Triticum aestivum L.) was chosen as a model species and was subjected to three environmentally relevant doses during germination and tiller development through root application. Morphological, physiological, and metabolic parameters were assessed. Despite a modest biomass decrease and alterations in membrane properties, no major impairments in germination or seedling development were observed. During tiller phase, both Fe3O4-NPs increased leaf length, and photosynthesis exhibited varied impacts: both Fe3O4-NPs and FORM alone increased pigments; only Fe3O4-NPs promoted gas exchange; all treatments improved the photochemical phase. Regarding oxidative stress, lipid peroxidation decreased in FORM and FORM@NMP, yet with increased O2-• in FORM@NMP; total flavonoids decreased in NH2@NMP and antioxidant enzymes declined across all materials. Phenolic profiling revealed a generalized trend towards a decrease in flavones. In conclusion, these nanoparticles can modulate wheat physiology/metabolism without apparently inducing phytotoxicity at low doses and during short-time exposure. ENVIRONMENTAL IMPLICATION: Iron-magnetic nanoparticles are widely used in environmental remediation and fertilization, besides of new applications continuously being developed, making them emerging contaminants. Soil is a major sink for these nanoparticles and their fate and potential environmental risks in ecosystems must be addressed to achieve more sustainable environmental applications. Furthermore, as the reuse of treated wastewater for agricultural irrigation is being claimed, it is of major importance to disclose the impact on crops of the nanoparticles used for wastewater decontamination, such as those proposed in this work.

The photophysical, photobiological, and DNA/HSA-binding properties of corroles containing carbazole and phenothiazine moieties.

This study characterized four corrole derivatives, namely Cbz-Cor, MetCbz-Cor, PTz-Cor, and PTzEt-Cor, examining their photophysical, electrochemical, photobiological, and biomolecule-binding properties. Experimental photophysical data of absorption and emission elements correlated with a theoretical analysis obtained through time-dependent density functional theory (TD-DFT). As for the photophysical properties, we observed lower fluorescence quantum yields and discernible differences between the excited and ground states, as indicated by Stokes shift values. Natural Transition Orbit (NTO) plots presented high occupied molecular orbital - low unoccupied molecular orbital (HOMO-LUMO) densities around the tetrapyrrolic macrocycle in all examples. Our findings demonstrate that corroles maintain stability in solution and offer photostability (<20 %), predominantly in DMSO(5 %)/Tris-HCl (pH 7.4) buffer solution. Furthermore, the singlet oxygen (1O2) quantum yield and log POW values underscore their potential application in photoinactivation approaches, as these corroles serve as effective ROS generators with more lipophilic features. We also evaluated their biomolecular binding capacity towards salmon sperm DNA and human serum albumin using spectroscopic techniques and molecular docking analysis for sustenance. Concerning biomolecule interaction profiles, the corrole derivatives showed a propensity for interacting in the minor grooves of the double helix DNA due to secondary forces, which were more pronounced in site III of the human serum protein.

Glutathione-Responsive Polymersome with Continuous Glutathione Depletion for Enhanced Photodynamic Therapy and Hypoxia-Activated Chemotherapy.

The high glutathione (GSH) level of the tumor microenvironment severely affects the efficacy of photodynamic therapy (PDT). The current GSH depletion strategies have difficulty meeting the dual needs of security and efficiency. In this study, we report a photosensitizer Chlorin e6 (Ce6) and hypoxia-activated prodrug tirapazamine (TPZ) coloaded cross-linked multifunctional polymersome (TPZ/Ce6@SSPS) with GSH-triggered continuous GSH depletion for enhanced photodynamic therapy and hypoxia-activated chemotherapy. At tumor sites, the disulfide bonds of TPZ/Ce6@SSPS react with GSH to realize decross-linking for on-demand drug release. Meanwhile, the generated highly reactive quinone methide (QM) can further deplete GSH. This continuous GSH depletion will amplify tumor oxidative stress, enhancing the PDT effect of Ce6. Aggravated tumor hypoxia induced by PDT activates the prodrug TPZ, resulting in an enhanced combination of PDT and hypoxia-activated chemotherapy. Both in vitro and in vivo results demonstrate the efficient GSH depletion and potent antitumor activities by TPZ/Ce6@SSPS. This work provides a strategy for the design of a continuous GSH depletion platform, which holds great promise for enhanced combination tumor therapy.

Oxygen Self-Supplied Perfluorocarbon-Modified Micelles for Enhanced Cancer Photodynamic Therapy and Ferroptosis.

Photodynamic therapy (PDT) and ferroptosis show significant potential in tumor treatment. However, their therapeutic efficacy is often hindered by the oxygen-deficient tumor microenvironment and the challenges associated with efficient intracellular drug delivery into tumor cells. Toward this end, this work synthesized perfluorocarbon (PFC)-modified Pluronic F127 (PFC-F127), and then exploits it as a carrier for codelivery of photosensitizer Chlorin e6 (Ce6) and the ferroptosis promoter sorafenib (Sor), yielding an oxygen self-supplying nanoplatform denoted as Ce6-Sor@PFC-F127. The PFCs on the surface of the micelle play a crucial role in efficiently solubilizing and delivering oxygen as well as increasing the hydrophobicity of the micelle surface, giving rise to enhanced endocytosis by cancer cells. The incorporation of an oxygen-carrying moiety into the micelles enhances the therapeutic impact of PDT and ferroptosis, leading to amplified endocytosis and cytotoxicity of tumor cells. Hypotonic saline technology was developed to enhance the cargo encapsulation efficiency. Notably, in a murine tumor model, Ce6-Sor@PFC-F127 effectively inhibited tumor growth through the combined use of oxygen-enhanced PDT and ferroptosis. Taken together, this work underscores the promising potential of Ce6-Sor@PFC-F127 as a multifunctional therapeutic nanoplatform for the codelivery of multiple cargos such as oxygen, photosensitizers, and ferroptosis inducers.