Photodynamic and Nail Penetration Enhancing Effects of Novel Multifunctional Photosensitizers Designed for The Treatment of Onychomycosis

Novel multifunctional photosensitizers (MFPSs), 5,10,15‐tris(4‐N‐methylpyridinium)‐20‐(4‐phenylthio)‐[21H,23H]‐porphine trichloride (PORTH) and 5,10,15‐tris(4‐N‐methylpyridinium)‐20‐(4‐(butyramido‐methylcysteinyl)‐hydroxyphenyl)‐[21H,23H]‐porphine trichloride (PORTHE), derived from 5,10,15‐Tris(4‐methylpyridinium)‐20‐phenyl‐[21H,23H]‐porphine trichloride (Sylsens B) and designed for treatment of onychomycosis were characterized and their functionality evaluated. MFPSs should function as nail penetration enhancer and as photosensitizer for photodynamic treatment (PDT) of onychomycosis. Spectrophotometry was used to characterize MFPSs with and without 532 nm continuous‐wave 5 mW cm^?2 laser light (± argon/mannitol/NaN₃). Nail penetration enhancement was screened (pH 5, pH 8) using water uptake in nails and fluorescence microscopy. PDT efficacy was tested (pH 5, ± argon/mannitol/NaN₃) in vitro with Trichophyton mentagrophytus microconida (532 nm, 5 mW cm^?2). A light‐dependent absorbance decrease and fluorescence increase were found, PORTH being less photostable. Argon and mannitol increased PORTH and PORTHE photostability; NaN₃ had no effect. PDT (0.6 J cm^?2, 2 μm ) showed 4.6 log kill for PORTH, 4.4 for Sylsens B and 3.2 for PORTHE (4.1 for 10 μm ). Argon increased PORTHE, but decreased PORTH PDT efficacy; NaN₃ increased PDT effect of both MFPSs whereas mannitol increased PDT effect of PORTHE only. Similar penetration enhancement effects were observed for PORTH (pH 5 and 8) and PORTHE (pH 8). PORTHE is more photostable, effective under low oxygen conditions and thus realistic candidate for onychomycosis PDT.     

Combined OX40 Agonist and PD-1 Inhibitor Immunotherapy Improves the Efficacy of Vascular Targeted Photodynamic Therapy in a Urothelial Tumor Model

Purpose: Vascular targeted photodynamic therapy (VTP) is a nonsurgical tumor ablation approach used to treat early-stage prostate cancer and may also be effective for upper tract urothelial cancer (UTUC) based on preclinical data. Toward increasing response rates to VTP, we evaluated its efficacy in combination with concurrent PD-1 inhibitor/OX40 agonist immunotherapy in a urothelial tumor-bearing model. Experimental design: In mice allografted with MB-49 UTUC cells, we compared the effects of combined VTP with PD-1 inhibitor/OX40 agonist with those of the component treatments on tumor growth, survival, lung metastasis, and antitumor immune responses. Results: The combination of VTP with both PD-1 inhibitor and OX40 agonist inhibited tumor growth and prolonged survival to a greater degree than VTP with either immunotherapeutic individually. These effects result from increased tumor infiltration and intratumoral proliferation of cytotoxic and helper T cells, depletion of Treg cells, and suppression of myeloid-derived suppressor cells. Conclusions: Our findings suggest that VTP synergizes with PD-1 blockade and OX40 agonist to promote strong antitumor immune responses, yielding therapeutic efficacy in an animal model of urothelial cancer.     

“Pointsource” Delivery of a Photosensitizer Drug and Singlet Oxygen: Eradication of Glioma Cells In Vitro

We describe a pointsource sensitizer‐tipped microoptic device for the eradication of glioma U87 cells. The device has a mesoporous fluorinated silica tip which emits singlet oxygen molecules and small quantities of pheophorbide sensitizer for additional production of singlet oxygen in the immediate vicinity. The results show that the device surges in sensitizer release and photokilling with higher rates about midway through the reaction. This was attributed to a self‐amplified autocatalytic reaction where released sensitizer in the extracellular matrix provides positive feedback to assist in the release of additional sensitizer. The photokilling of the glioma cells was analyzed by global toxicity and live/dead assays, where a killing radius around the tip with ~0.3 mm precision was achieved. The implication of these results for a new PDT tool of hard‐to‐resect tumors, e.g. in the brain, is discussed.     

Photophysics of Glycosylated Derivatives of a Chlorin,Isobacteriochlorin and Bacteriochlorin for Photodynamic Theragnostics: Discovery of a Two‐photon‐absorbing Photosensitizer

The photophysical properties of a chlorin, isobacteriochlorin and bacteriochlorin built on a core tetrapentafluorophenylporphyrin (TPPF₂₀) and the nonhydrolyzable para thioglycosylated conjugates of these chromophores are presented. The photophysical characterization of these compounds was done in three different solvents to correlate with different environments in cells and tissues. Compared with TPPF₂₀ other dyes have greater absorption in the red region of the visible spectrum and greater fluorescence quantum yields. The excited state lifetimes are from 3 to 11 ns. The radiative and nonradiative rate constants for deactivation of the excited state were estimated from the fluorescence quantum yield and excited state lifetime. The data indicate that the bacteriochlorin has strong absorption bands near 730 nm and efficiently enters the triplet manifold. The isobacteriochlorin has a 40–70% fluorescence quantum yield depending on solvent, so it may be a good fluorescent tag. The isobacteriochlorins also display enhanced two‐photon absorption, thereby allowing the use of 860 nm light to excite the compound. While the two‐photon cross section of 25 GM units is not large, excitation of low chromophore concentrations can induce apoptosis. The glycosylated compounds accumulate in cancer cells and a head and neck squamous carcinoma xenograft tumor model in mice. These compounds are robust to photobleaching.     

Photosensitizer initiated attacks on DNA under dry conditions and their inhibition: a DNA archiving issue

Long-term aging of dry DNA is thought to be due to the attack of diverse cascades of reactive species with probably, no one single initiator of the cascades explaining all circumstances. Photosensitizer-initiated reactions from methylene blue and riboflavin were used to generate two model systems of reactive species around dry DNA in order to understand such systems and how to block them. Damage was assessed using plasmid DNA as a substrate with an in-situ microgel electrophoretic technique. Photodynamic methylene blue damage to DNA was very oxygen dependent but not that of riboflavin. This indicates that indirect type II pathways, probably via singlet oxygen were important for methylene blue but not for riboflavin. In both the absence and presence of oxygen, the DNA protection offered by dry caffeine and urate to both photodynamic agents indicated that most DNA attack was via electrophilic species. Overall, protection of dry archived DNA from spontaneously reactive species such as free radicals appears to be a real issue and, as expected, the predominant species in air appear to involve oxygen but not exclusively or necessarily so.     

Effect of Delivery System on the Pharmacokinetics and Tissue Distribution of bis(Di-lsobutyl Octadecylsiloxy)Silicon 2,3-Naphthalocyanine (isoBOSINC), a Photosensitizer for Tumor Therapy

Abstract— Bis(di-isobutyl octadecylsiloxy)silicon 2,3-naphthalocy-anine (isoBOSINC) is a representative of a group of naphthalocyanine derivatives with spectral and photophysical properties that make them attractive candidates for photodynamic therapy (PDT). Tissue distributions were studied in tumor-bearing rats as a function of delivery system and time following administration. The tumor model was an N-(4-[5-nitro-2-furyl]-2-thiazolyl) formamide (FANFT)-induced urothelial cell carcinoma transplanted into one hind leg of male Fischer 344 rats; isoBOSINC was delivered to the rats by intravenous injection of 0.50 mg/kg of body weight as a suspension either in 10% Tween 80 in saline (Tween) or 10% (Cremophor® EL + propylene glycol) in saline (Cremophor). The isoBOSINC was isolated from several tissues and organs, as well as tumors and peritumoral muscles and skin. Quantitation was by a high-performance liquid chromatographic technique with detection that utilizes the native fluorescence of the naphthalocyanine derivative. Independent of the delivery system, the dye was retained in tumors at higher concentrations than in normal tissues, except for spleen and liver. The isoBOSINC retention in tumors was high and was vehicle dependent. For Tween, the maximal ratio of dye in tumor versus peritumoral muscle occurred 12 h after injection; for Cremophor, the maximal ratio occurred later, 336 h postinjection. When the drug was delivered in Tween, isoBOSINC in serum showed two compartment kinetics: half-lives of about 2 and 11 h were found for the distribution and the elimination phases, respectively. When Cremophor was the vehicle, the elimination half-life was about 20 h, and one compartment kinetics was observed. The latter findings may explain the generally higher levels of the dye attained by the tissues at later times with Cremophor as the vehicle. An interesting exception wasthat after 7 and 14 days postinjection in Tween, the levels of dye found in testes were six- to seven-fold higher than those found after Cremophor delivery. Levels of dye were very low or not detectable in the brain. Optimal parameters for PDT of tumors with this novel photosensitizer are clearly time- and vehicle-dependent, and future PDT studies will need to incorporate these modulators.     

The Effects of a Strong Disaggregating Agent on Sec-Page of Aquatic and Soil Humic Matter

Abstract

Size-exclusion chromatographic (SEC) fractionation and electrophoretic separation of aquatic humic matter samples from a Finnish lake using Sephadex G-75 with 7 M urea solution as eluent and 10% polyacrylamide gel (PAGE) with urea and sodium dodecyl sulphate solution (SDS), respectively, were performed and compared to similar analyses performed on a Russian chernozem soil humic acid sample and Nordic reference fulvic and humic acid samples. The integrated whole of aquatic humic solutes and soil humic acids were found to exhibit similar SEC-PAGE behaviours. Humic matter was not excessively disaggregated by the 7 M urea and hence SEC-PAGE can with confidence be applied as a coarse, initial fractionation procedure or for certain predeterminations of the structural composition.     

Microhydration Effects on the Ultrafast Photodynamics of Cytosine: Evidences for a Possible Hydration‐Site Dependence

Ultrafast excited‐state deactivation dynamics of small cytosine (Cy) and 1‐methylcytosine (1mCy) microhydrates, Cy?(H₂O)_1‐3 and 1mCy?(H₂O)_1,2, produced in a supersonic expansion have been studied by mass‐selected femtosecond pump–probe photoionization spectroscopy at about 267 nm excitation. The seeded supersonic expansion of Ar/H₂O gas mixtures allowed an extensive structural relaxation of Cy and 1mCy microhydrates to low‐energy isomers. With the aid of electronic structure calculations, we assigned the observed ultrafast dynamics to the dominant microhydrate isomers of the amino‐keto tautomer of Cy and 1mCy. Excited‐state lifetimes of Cy?(H₂O)_1‐3 measured here are 0.2–0.5 ps. Comparisons of the Cy?H₂O and 1mCy?H₂O transients suggest that monohydration at the amino Watson–Crick site induces a substantially stronger effect than at the sugar‐edge site in accelerating excited‐state deactivation of Cy.     

Binding and Sulfonation of Poly(acrylic acid) on Iron Oxide Nanoparticles: a Novel,Magnetic, Strong Acid Cation Nano‐Adsorbent

Summary: A novel, magnetic, strong acid cation nano‐adsorbent has been developed by the covalent binding of poly(acrylic acid) on the surface of Fe₃O₄ nanoparticles followed by sulfonation using sulfanilic acid via carbodiimide activation. The nano‐absorbent can be easily recovered or manipulated with an external magnetic field and shows a good capacity for the rapid and efficient adsorption of multivalent metal cations from aqueous solutions.

An illustration for the binding and sulfonation of PAA on Fe₃O₄ nanoparticles to produce a magnetic, strong acid cation nano‐adsorbent.     

A Comparison of the Photodynamic Effects of Temoporfin (mTHPC) and MC540 on Leukemia Cells: Efficacy and Apoptosis

The photodynamic effects of temoporfin (meso-tetrahy-droxyphenylchlorin, mTHPC) and merocyanine 540 (MC540) in murine myeloid leukemia M1 and WEHI 3B (JCS) cells were compared. The mTHPC was found to be more potent and selective. At a lethal dosage of 90% killing (LD90), only 1.3 μM of mTHPC and 4.2 kj/m2 of light irradiation was required, which was a 20-fold lower drug concentration and 11-fold smaller light dose than that required when using MC540. Meanwhile, three times less, or 15%, of the coincubated erythrocytes were destroyed by mTHPC than by MC540. Confocal micrographs showed that both drugs accumulated diffusely inside the cytoplasm in a very similar fashion, but mTHPC induced a more extensive apoptosis in photosensitized JCS cells. For example, at LD90, mTHPC practically killed all JCS cells via apoptosis and cleaved the DNA to extremely small 150 base-pair fragments. In contrast, among the JCS cells killed by MC540, about 88% died via apoptosis and large DNA fragments were abundant. Relative to MC540, the ability of mTHPC to trigger large-scale and thorough apoptosis in leukemia cells may help explain its potency and selectivity.     

低剂量长期补充微量元素治疗“多发性纤维脂肪血管瘤病”一例

阐述了一例“多发性纤维脂肪血管瘤病”患者,经十四个月以上的低剂量多种微量元素制剂治疗,达到良好的治疗效果。     

环境友好新材料的开发:微波法研制固体强碱及其在油品脱硫醇中的应用

用微波辐射能将MgO等氧化物负载在NaY等分子筛及SiO₂的表面上,形成具有强碱性和高比表面的复合新材料,并实现了制备过程中的”零排放“而成为环境友好新工艺。本文探讨了沸石孔结构、表面含水量以及客体性质对于微波法制备样品的影响,并探讨了新型固体强碱在汽油脱硫酸工艺中的应用。     

环境友好新材料的开发:微波法研制固体强碱及其在油品脱硫醇中的应用

用微波辐射能将ＭｇＯ等氧化物负载在ＮａＹ等分子筛及ＳｉＯ_２的表面上,形成具有强碱性和高比表面的复合新材料,并实现了制备过程中的“零排放”而成为环境友好新工艺。本文探讨了沸石孔结构、表面含水量以及客体性质对于微波法制备样品的影响,并探讨了新型固体强碱在汽油脱硫酸工艺中的应用。     

The Antiproliferative and Apoptotic Effects of a Novel Quinazoline Carrying Substituted-Sulfonamides: In Vitro and Molecular Docking Study

In order to investigate for a new effective and safe anticancer drug, we synthesized a novel series of quinazoline containing biologically active substituted-sulfonamide moiety at 3- position 4a–n. The structure of the newly prepared compounds was proved by microanalysis, IR, ¹H-NMR, ¹³C-NMR and mass spectral data. All the synthesized compounds were evaluated for their in vitro cytotoxic activity in numerous cancer cell lines including A549, HepG-2, LoVo and MCF-7 and normal HUVEC cell line. The two most active compounds 4d and 4f were then tested for their apoptosis induction using DNA content and Annexin V-FITC/PI staining. Moreover, apoptosis initiation was also confirmed using RT-PCR and Western blot. To further understand the binding preferences of quinazoline sulfonamides, docking simulations were used. Among the fourteen new synthesized compounds, we found that compounds 4d and 4f exerted the strongest cytotoxicity against MCF-7 cells with an IC₅₀ value of 2.5 and 5 μM, respectively. Flow cytometry data revealed the ability of compounds 4d and 4f to mediate apoptosis and arrest cell cycle growth at G1 phase. Furthermore, RT-PCR and Western blot results suggested that both 4d and 4f activates apoptotic cell death pathway in MCF-7 cells. Molecular docking assessments indicated that compounds 4d and 4f fit perfectly into Bcl2’s active site. Based on the biological properties, we conclude that both compounds 4d and 4f could be used as a new type of anticancer agent, which provides a scientific basis for further research into the treatment of cancer.     

Effects of a Novel Organic Alkali on the Interfacial Tension and Emulsification Behaviors Between Crude Oil and Water

Experiments have been carried out to investigate the interfacial tension (IFT) and emulsification behaviors between Shengli crude oil and a novel organic alkali (OA). The dynamic IFT and minimum IFT are adopted to characterize the IFT behaviors; the microscopic method, Turbiscan stability index, separated water rate, and laser particle size analysis method are used to show the emulsification behaviors. The dynamic and minimum IFT both decrease continuously with the increase of OA concentration whether surfactant is added or not; because of the synergy of OA and surfactant, the minimum IFT will be reduced to the ultralow value. The synergy is also crucial for the crude oil emulsification. When OA and surfactant are used together, owing to the mosaic and cross-multiple adsorption of OA, surfactant and in situ soap at the interfacial film, the oil can be emulsified more easily, the quantity of emulsified droplets is higher, and the emulsion is more stable with OA concentration increases. The relationship of the minimum IFT and emulsification is investigated; it indicates that the emulsion stability improves, the degree of dispersed homogeneity of oil droplets increases, and the median diameter of emulsified oil droplets decreases with the decline of the minimum IFT.     

电子电镀铜新体系中添加剂对铜电沉积及镀层结构的影响机制

以低主盐浓度、 弱碱性、 复合配位的柠檬酸盐电子电镀铜新体系为研究对象, 阐明了新型添加剂XNS(聚胺类化合物和含氮化合物的混合物)在新电沉积铜体系中的作用. 恒电流沉积实验结果表明, 添加剂XNS能够提高铜沉积的电流效率, 特别是在2.0 A/dm²电流密度下, 添加剂XNS使铜沉积电流效率达到95.4%, 提高了17.5%. 电化学实验的结果表明, 添加剂XNS改变了铜沉积的电极过程, 由原来的两步单电子还原过程 [Cu(Ⅱ)+e→Cu(Ⅰ)+e→Cu]转变为一步两电子还原过程[Cu(Ⅱ)+2e→Cu]. 虽然添加剂XNS呈现促进铜电沉积的特征, 即还原电流增大, 但铜镀层颗粒却更细小、 更致密均匀. 在2.0 A/dm²电流密度下, 铜镀层晶体结构由无添加剂时的(111)晶面重构为高择优取向的(200)晶面.     

Photophysical and Redox Properties of a Series of Phthalocyanines: Relation with Their Photodynamic Activities on TF-1 and Daudi Leukemic Cells

Abstract— The photodynamic therapy (PDT) efficiency of five phthalocyanines, chloroaluminum phthalocyanine (AlPc), dichlorosilicon phthalocyanine (SiPc), bis (tri- n -hexylsi-loxy)silicon phthalocyanine (PcHEX), bis (triphenyl-siloxy)silicon phthalocyanine (PcPHE) and nickel phthalocyanine (NiPc), was assessed on two leukemic cell lines TF-1 and erythroieukemic and B lymphoblastic cell lines, Daudi, respectively. AlPc showed the best photocytotox-icity leading to 0.008 surviving fraction at 2 × 10⁻⁹ M for TF-1 and 4 × 10⁻⁹ M for Daudi. At 5 × 10⁻⁷ M , SiPc and PcHEX induced a significant photokilling, whereas NiPc and PcPHE were inactive. Laser flash photolysis and photoredox properties of the phthalocyanines were investigated to try to relate these parameters with the biological effects. AlPc showed the longest triplet lifetime: 484 fis in dimethyl sulfoxide/H₂O. This value was increased up to 820 u.s when AlPc was complexed with human serum albumin used as a membrane model. Such an enhancement was not observed with the silicon phthalocyanines. Upon irradiation, all the phthalocyanines generated singlet oxygen with 0.29–0.37 quantum yield values. The reduction potentials of the excited states obtained from measurement in the ground state and energy of the excited triplets show that AlPc is the best electron acceptor. The in vitro photocytotoxicity observed and the measured parameters are in agreement with a key role of electron transfer in PDT assays involving these phthalocyanines.