Light-Activated Biodegradable Covalent Organic Framework-Integrated Heterojunction for Photodynamic, Photothermal, and Gaseous Therapy of Chronic Wound Infection.

Chronic wound healing, impeded by bacterial infections and drug resistance, poses a threat to global human health. Antibacterial phototherapy is an effective way to fight microbial infection without causing drug resistance. Covalent organic frameworks (COFs) are a class of highly crystalline functional porous carbon-based materials composed of light atoms (e.g., carbon, nitrogen, oxygen, and borane), showing potential applications in the biomedical field. Herein, we constructed porphyrin-based COF nanosheets (TP-Por CON) for synergizing photodynamic and photothermal therapy under red light irradiation (e.g., 635 nm). Moreover, a nitric oxide (NO) donor molecule, BNN6, was encapsulated into the pore volume of the crystalline porous framework structure to moderately release NO triggered by red light irradiation for realizing gaseous therapy. Therefore, we successfully synthesized a novel TP-Por CON@BNN6-integrated heterojunction for thoroughly killing Gram-negative bacteria Escherichia coli and Gram-positive bacteria Staphylococcus aureus in vitro. Our research identified that TP-Por CON@BNN6 has favorable biocompatibility and biodegradability, low phototoxicity, anti-inflammatory properties, and excellent mice wound healing ability in vivo. This study indicates that the TP-Por CON@BNN6-integrated heterojunction with multifunctional properties provides a potential strategy for COF-based gaseous therapy and microorganism-infected chronic wound healing.

Anisotropic Truncated Octahedral Au with Pt Deposition on Arris for Localized Surface Plasmon Resonance-Enhanced Photothermal and Photodynamic Therapy of Osteosarcoma.

The multifunctional combined nanoplatform has a wide application prospect in the synergistic treatment of cancer. Nevertheless, the traditional treatment of phototherapy is limited by the catalytic nanomaterial itself, so the effect is not satisfactory. Here, the arris of the anisotropic truncated octahedral Au (TOh Au) was coated with noble metal Pt to form a spatial separation structure, which enhanced the local surface plasmonic resonance and thus boosted the photocatalytic effect. In this system, the highly efficient photocatalysis provides a strong guarantee for oncotherapy. On the one hand, the structure of arris deposition adequately improves the efficiency of photothermal conversion, which substantially improves the effectiveness of photothermal therapy. On the other hand, in situ oxygen production of Pt ameliorates tumor hypoxia, and through the O2 self-production and sales mode, the growth and development of tumor were inhibited. Meanwhile, under the enhanced photocatalysis, more O2 were produced, which greatly evolved the treatment effect of photodynamic therapy. In the end, the addition of hyaluronic acid can specifically target osteosarcoma cells while improving the retention time and biocompatibility of the material in the body. Thus, the nanocomposite shows superexcellent synergistic enhancement of photothermal conversion efficiency and photodynamic capability in vitro and in vivo, which provides a potential possibility for osteosarcoma cure.

Recent Advances in Porphyrin-Based Inorganic Nanoparticles for Cancer Treatment.

The application of porphyrins and their derivatives have been investigated extensively over the past years for phototherapy cancer treatment. Phototherapeutic Porphyrins have the ability to generate high levels of reactive oxygen with a low dark toxicity and these properties have made them robust photosensitizing agents. In recent years, Porphyrins have been combined with various nanomaterials in order to improve their bio-distribution. These combinations allow for nanoparticles to enhance photodynamic therapy (PDT) cancer treatment and adding additional nanotheranostics (photothermal therapy-PTT) as well as enhance photodiagnosis (PDD) to the reaction. This review examines various porphyrin-based inorganic nanoparticles developed for phototherapy nanotheranostic cancer treatment over the last three years (2017 to 2020). Furthermore, current challenges in the development and future perspectives of porphyrin-based nanomedicines for cancer treatment are also highlighted.

Simultaneous Unlocking Optoelectronic and Interfacial Properties of C60 for Ultrasensitive Immunosensing by Coupling to Metal-Organic Framework.

Due to exceptional electron-accepting ability, light-absorption, and a delocalized conjugated structure, buckminsterfullerene (C60) has attracted fascinating interest in the field of organic solar cells. However, poor delocalization and accumulation of electrons for pristine C60 in physiological aqueous solution and difficulties in conjugation with biomolecules limit its extended photovoltaic applications in bioassay. Herein, we reported the noncovalent coupling of C60 to an electronically complementary porphyrin-derived metal-organic framework (PCN-224) with carboxyl-group terminals. Such assembly not only offered a friendly interface for bioconjugation but also resulted in a long-range ordering C60@PCN-224 donor-acceptor system that demonstrated an unprecedented photocurrent enhancement up to 10 times with respect to each component. As an example, by further cooperating with Nanobodies, the as-prepared C60@PCN-224 was applied to a photoelectrochemical (PEC) immunosensor for S100 calcium-binding protein B with by far the most promising detection activities. This work may open a new venue to unlock the great potential of C60 in PEC biosensing with excellent performances.

Image-guided photo-therapeutic nanoporphyrin synergized HSP90 inhibitor in patient-derived xenograft bladder cancer model.

Photodynamic therapy is a promising and effective non-invasive therapeutic approach for the treatment of bladder cancers. Therapies targeting HSP90 have the advantage of tumor cell selectivity and have shown great preclinical efficacy. In this study, we evaluated a novel multifunctional nanoporphyrin platform loaded with an HSP90 inhibitor 17AAG (NP-AAG) for use as a multi-modality therapy against bladder cancer. NP-AAG was efficiently accumulated and retained at bladder cancer patient-derived xenograft (PDX) over 7 days. PDX tumors could be synergistically eradicated with a single intravenous injection of NP-AAG followed by multiple light treatments within 7 days. NP-AAG mediated treatment could not only specifically deliver 17AAG and produce heat and reactive oxygen species, but also more effectively inhibit essential bladder cancer essential signaling molecules like Akt, Src, and Erk, as well as HIF-1α induced by photo-therapy. This multifunctional nanoplatform has high clinical relevance and could dramatically improve management for bladder cancers with minimal toxicity.

Chemical antagonism between photodynamic agents and chemotherapeutics: mechanism and avoidance.

We report a photochemical reaction-induced antagonism between the photodynamic agent (PS) and anti-cancer drugs during combined therapy. The annihilation of singlet oxygen and alkene-containing drugs into inactive drug hydroperoxides is responsible for the antagonism, and results in decreased efficacy against several cancer cell lines. Experimental and simulation results reveal that the annihilation abates with increasing distance between the PS and drugs via confining the PS and drugs into separated vehicles. As a result, antagonism can be switched to synergism in treating both drug sensitive and resistant cancer cells.

Self-assembled porphyrin nanodiscs with structure-dependent activation for phototherapy and photodiagnostic applications.

The abilities to deliver and subsequently activate a therapeutic at the intended site of action are two important challenges in the synthesis of novel nanoparticles. Poor tumor permeability as a result of a dense microenvironment can impede the delivery of nanoparticles to the site of action. The design of a sub-40 nm activatable porphyrin nanodisc, based on protein-induced lipid constriction, is described. The biophotonic nanoparticle, self-assembled from aggregated porphyrin-lipid, is stabilized by an amphipathic alpha helical protein and becomes photoactive when its structure is perturbed. Enzymatic cleavage of the constricting protein leads to conversion of the particle from a disc- to a vesicle-shaped structure and provides further evidence that the apolipoprotein serves a functional role on the nanodisc. Fluorescence measurements of these nanodiscs in a detergent show that fluorescence is over 99% quenched in the intact state with a 12-fold increase in singlet oxygen generation upon disruption. Cellular fluorescence unquenching and dose-dependent phototoxicity demonstrate that these nanodiscs can be internalized and unquenched intracellularly. Finally, nanodiscs were found to display a 5-fold increase in diffusion coefficient when compared with the protein-free control ((3.5±0.1)×10(-7) vs (0.7±0.03)×10(-7) cm2 s(-1)). The ability to incorporate large amounts of photosensitizer drugs into its compact structure allows for phototherapeutic action, fluorescence diagnostic applications, and the potential to effectively deliver photosensitizers deep into poorly permeable tumors.

Water-soluble porphyrin-polyethylene glycol conjugates with enhanced cellular uptake for photodynamic therapy.

Water soluble porphyrins were designed and prepared by Williamson ether synthesis reaction between tetrakis(p-bromomethylphenyl)porphyrin and polyethylene glycol (PEG) for photodynamic therapy. The quantum yields for the generation of singlet oxygen of tetra-polyethylene glycol branched porphyrin shows above 80% in D2O. Luminescence of singlet state oxygen was observed from D2O solution under the single-photon excitation at 514 nm. In vitro test, cellular uptake efficiency has been enhanced by simple modification of molecular structure through changing the number of PEG unit without any support such as polymer-encapsulated inorganic nanoparticles.

The effect of photodynamic treatment combined with antibiotic action or host defence mechanisms on Staphylococcus aureus biofilms.

Staphylococcus aureus is one of the most important etiological agents of infections associated with medical devices. This is in part due to the ability of the organism to form biofilm, which provides a microenvironment that protects from attack by the host's immune system and by antibiotics. In this study we examined the structure of polysaccharide intercellular adhesin (PIA)-dependent or protein-based S. aureus biofilms. We defined new strategies aimed at treatment of mature established biofilms using photodynamic treatment (PDT) combined with chemotherapy or phagocytosis. Significant inactivation of bacteria was observed when structurally distinct biofilms were exposed to the cationic porphyrin, tetra-substituted N-methyl-pyridyl-porphine (TMP), and simultaneously to visible light. Moreover, PDT-treated biofilms exposed to vancomycin or subjected to the phagocytic action of whole blood resulted in their almost complete eradication. The drastic reduction in staphylococcal survival and the disruption of biofilms were confirmed by confocal laser scanning microscopy and scanning electron microscopy. The results suggest that PDT combined with vancomycin and the host defences may be a useful approach for the inactivation of staphylococcal biofilms adhering to medical implant surfaces.

Light-harvesting supramolecular porphyrin macrocycle accommodating a fullerene-tripodal ligand.

Trisporphyrinatozinc(II) (1-Zn) with imidazolyl groups at both ends of the porphyrin self-assembles exclusively into a light-harvesting cyclic trimer (N-(1-Zn)(3)) through complementary coordination of imidazolyl to zinc(II). Because only the two terminal porphyrins in 1-Zn are employed in ring formation, macrocycle N-(1-Zn)(3) leaves three uncoordinated porphyrinatozinc(II) groups as a scaffold that can accommodate ligands into the central pore. A pyridyl tripodal ligand with an appended fullerene connected through an amide linkage (C(60)-Tripod) was synthesized by coupling tripodal ligand 3 with pyrrolidine-modified fullerene, and this ligand was incorporated into N-(1-Zn)(3). The binding constant for C(60)-Tripod in benzonitrile reached the order of 10(8) M(-1). This value is ten times larger than those of pyridyl tetrapodal ligand 2 and tripodal ligand 3. This behavior suggests that the fullerene moiety contributes to enhance the binding of C(60)-Tripod in N-(1-Zn)(3). The fluorescence of N-(1-Zn)(3) was almost completely quenched (approximately 97 %) by complexation with C(60)-Tripod, without any indication of the formation of charge-separated species or a triplet excited state of either porphyrin or fullerene in the transient absorption spectra. These observations are explained by the idea that the fullerene moiety of C(60)-Tripod is in direct contact with the porphyrin planes of N-(1-Zn)(3) through fullerene-porphyrin pi-pi interactions. Thus, C(60)-Tripod is accommodated in N-(1-Zn)(3) with a pi-pi interaction and two pyridyl coordinations. The cooperative interaction achieves a sufficiently high affinity for quantitative and specific introduction of one equivalent of tripodal guest into the antenna ring, even under dilute conditions ( approximately 10(-7) M) in polar solvents such as benzonitrile. Additionally, complete fluorescence quenching of N-(1-Zn)(3) when accommodating C(60)-Tripod demonstrates that all of the excitation energy collected by the nine porphyrins migrates rapidly over the macrocycle and then converges efficiently on the fullerene moiety by electron transfer.

[Pulsed dye laser treatment of acne. Study of clinical efficacy and mechanism of action]. / Láser de colorante pulsado en el tratamiento del acné. Estudio de la eficacia clínica y mecanismo de acción.

INTRODUCTION: Acne vulgaris is a multifactorial disease of the pilosebaceous unit characterized by the development of inflammatory (papules, pustules, cysts) and/or non inflammatory lesions (open and closed comedones) that may progress to scars. The increase of bacterial resistances, adverse effects and teratogenicity of retinoids and lack of response to usual therapies have led to investigate new therapeutic alternatives for acne. MATERIAL AND METHOD: We studied 36 patients with mild to moderate acne vulgaris. We performed treatment every 4 weeks using pulsed dye laser therapy with a wavelength of 585 nm and pulse duration of 350 microseconds. RESULTS: At twelve weeks of treatment a decrease of 27 % of non inflammatory lesions and of 57 % of active lesions was observed. Treatment was well tolerated and considered positive, in terms of healing, in 25 patients. CONCLUSIONS: Pulse dye laser therapy mainly improves inflammatory lesions of acne with few adverse effects.

Tumor vascular permeabilization by vascular-targeting photosensitization: effects, mechanism, and therapeutic implications.

PURPOSE: Loss of vascular barrier function has been observed shortly following vascular-targeting photodynamic therapy. However, the mechanism involved in this event is still not clear, and the therapeutic implications associated with this pathophysiologic change have not been fully explored. EXPERIMENTAL DESIGN: The effect of vascular-targeting photodynamic therapy on vascular barrier function was examined in both s.c. and orthotopic MatLyLu rat prostate tumor models and endothelial cells in vitro, using photosensitizer verteporfin. Vascular permeability to macromolecules (Evans blue-albumin and high molecular weight dextran) was assessed with dye extraction (ex vivo) and intravital microscopy (in vivo) methods. Intravital microscopy was also used to monitor tumor vascular functional changes after vascular-targeting photodynamic therapy. The effects of photosensitization on monolayer endothelial cell morphology and cytoskeleton structures were studied with immunofluorescence staining. RESULTS: Vascular-targeting photodynamic therapy induced vascular barrier dysfunction in the MatLyLu tumors. Thus, tumor uptake of macromolecules was significantly increased following photodynamic therapy treatments. In addition to vascular permeability increase, blood cell adherence to vessel wall was observed shortly after treatment, further suggesting the loss of endothelial integrity. Blood cell adhesion led to the formation of thrombi that can occlude blood vessels, causing vascular shutdown. However, viable tumor cells were often detected at tumor periphery after vascular-targeting photodynamic therapy. Endothelial cell barrier dysfunction following photodynamic therapy treatment was also observed in vitro by culturing monolayer endothelial cells on Transwell inserts. Immunofluorescence study revealed microtubule depolymerization shortly after photosensitization treatment and stress actin fiber formation thereafter. Consequently, endothelial cells were found to retract, and this endothelial morphologic change led to the formation of intercellular gaps. CONCLUSIONS: Vascular-targeting photodynamic therapy permeabilizes blood vessels through the formation of endothelial intercellular gaps, which are likely induced via endothelial cell microtubule depolymerization following vascular photosensitization. Loss of endothelial barrier function can ultimately lead to tumor vascular shutdown and has significant implications in drug transport and tumor cell metastasis.

Enhancement of the photodynamic activity of tri-cationic porphyrins towards proliferating keratinocytes by conjugation to poly-S-lysine.

A fast uptake of the tri-cationic 5-(4-carboxyphenyl)-10,15,20-tris(4-methylpyridinium-4-yl)porphyrin tri-iodide (P-H), independent of the presence or absence of proteins in the culture medium, occurs during incubation of NCTC 2544 human keratinocytes with this porphyrin. By contrast, the uptake of the poly-S-lysine conjugate (P-(Lys)(n)) is faster in serum-free medium than in the supplemented medium suggesting that P-(Lys)(n) interacts with serum proteins. The P-(Lys)(n) uptake is almost an order of magnitude greater than that of P-H in serum-free or supplemented culture medium. With histidine as a specific probe of type II photodynamic reactions, the relative photosensitizing effectiveness of the conjugate is only one fourth that of P-H. Nevertheless, the photocytotoxicity of the conjugate is strongly enhanced as compared to that of P-H as a result of its larger uptake. Thus, the doses achieving 50% of photocytotoxicity after incubation with 5 microM of the conjugate and its parent cationic porphyrin are about 20 min and 1 h, respectively. Similarly, the initial rate of the cell lipid peroxidation induced by photosensitization with P-(Lys)(n) is about 8 times higher than that obtained with P-H. Fluorescence microscopy reveals that P-H is more diffusely located in the cytoplasm than P-(Lys)(n) which seems to accumulate in lysosome-like structures. Little if any staining of the nucleus is observed with both photosensitizers.

[The mechanisms of the porphyrin conformation of normal blood hemoglobin and in pathology]. / Mekhanizmy konformatsii porfirinov gemoglobina krovi v norme i pri patologii.

The spectra of resonance Raman scattering of blood in norm and under pathology (myocardial infarction and sepsis), as well after artificial hemotransfusion or UV photomodification have been studied. It has been shown that under heart pathology the structure of hemoglobin porphyrin macrocycle of erythrocytes changes, the size of porphyrin "nucleus" increases. The opposite conditions are observed at blood sepsis. It has been found that the traditional methods in tissue restoration, hemotransfusion and UV photomodification of blood don't result in complete restoration of hemoporphyrin molecule.

Photophysics and photochemistry of new verdin compounds.

Five different verdins, including one zinc metal chelate, were examined by laser flash techniques. Triplet molar absorption coefficients, triplet and singlet oxygen quantum yields and triplet lifetimes were determined. Zinc methyl pyroverdin (ZNMPV), copro II verdin trimethyl ester (CVTME) and deuteroverdin methyl ester (DVME) have the highest triplet and singlet oxygen quantum yields. ZNMPV and CVTME have the longest triplet lifetimes. Our data are consistent with singlet oxygen as the primary modality for phototherapy and it is suggested that DVME and CVTME may be useful agents.

Inactivation of erythrocytic, lymphocytic and myelocytic leukemic cells by photoexcitation of endogenous porphyrins.

The photodynamic sensitization of leukemic cells (erythrocytic, myelocytic and lymphocytic) via light activation of endogenous porphyrins is described. Human myelocytic-erythrocytic K562 cells and murine Friend erythroleukemia (FELC) and T-cell lymphoma Eb-Esb cells were stimulated to synthesize and accumulate porphyrins. K562 cells accumulated high amounts of protoporphyrin by stimulation with 5-aminolevulinic acid (ALA) plus sodium butyrate or hemin. For Friend and Eb-Ebs cells ALA was an adequate stimulator. The high-metastatic Esb lymphoma cells accumulated comparatively more porphyrin than the low-metastatic Eb cell line. Maximal porphyrin accumulation produced mortality rates of more than 99% after 10 min of photoactivation of the three leukemic lines. Thymidine incorporation was inhibited by the photodynamic effect depending on porphyrin concentration. These results confirm the photodynamic ability of endogenous porphyrins to inactivate cancer cells of different origins.