Innovative Strategies for Hypoxic‐Tumor Photodynamic Therapy

Despite its clinical promise, photodynamic therapy (PDT) suffers from a key drawback associated with its oxygen‐dependent nature, which limits its effective use against hypoxic tumors. Moreover, both PDT‐mediated oxygen consumption and microvascular damage further increase tumor hypoxia and, thus, impede therapeutic outcomes. In recent years, numerous investigations have focused on strategies for overcoming this drawback of PDT. These efforts, which are summarized in this review, have produced many innovative methods to avoid the limits of PDT associated with hypoxia.     

Spectroelectrochemical and computational studies on the mechanism of hypoxia selectivity of copper radiopharmaceuticals

Detailed chemical, spectroelectrochemical and computational studies have been used to investigate the mechanism of hypoxia selectivity of a range of copper radiopharmaceuticals. A revised mechanism involving a delicate balance between cellular uptake, intracellular reduction, reoxidation, protonation and ligand dissociation is proposed. This mechanism accounts for observed differences in the reported cellular uptake and washout of related copper bis(thiosemicarbazonato) complexes. Three copper and zinc complexes have been characterised by X-ray crystallography and the redox chemistry of a series of copper complexes has been investigated by using electronic absorption and EPR spectroelectrochemistry. Time-dependent density functional theory (TD-DFT) calculations have also been used to probe the electronic structures of intermediate species and assign the electronic absorption spectra. DFT calculations also show that one-electron oxidation is ligand-based, leading to the formation of cationic triplet species. In the absence of protons, metal-centred one-electron reduction gives the reduced anionic copper(I) species, [CuIATSM](-), and for the first time it is shown that molecular oxygen can reoxidise this anion to give the neutral, lipophilic parent complexes, which can wash out of cells. The electrochemistry is pH dependent and in the presence of stronger acids both chemical and electrochemical reduction leads to quantitative and rapid dissociation of copper(I) ions from the mono- or diprotonated complexes, [CuIATSMH] and [Cu(I)ATSMH2]+. In addition, a range of protonated intermediate species have been identified at lower acid concentrations. The one-electron reduction potential, rate of reoxidation of the copper(I) anionic species and ease of protonation are dependent on the structure of the ligand, which also governs their observed behaviour in vivo.     

Analytical artefacts in the speciation of arsenic in clinical samples

Urine and blood samples of cancer patients, treated with high doses of arsenic trioxide were analysed for arsenic species using HPLC-HGAFS and, in some cases, HPLC-ICPMS. Total arsenic was determined with either flow injection-HGAFS in urine or radiochemical neutron activation analysis in blood fractions (in serum/plasma, blood cells). The total arsenic concentrations (during prolonged, daily/weekly arsenic trioxide therapy) were in the μg mL⁻¹ range for urine and in the ng g⁻¹ range for blood fractions. The main arsenic species found in urine were As(III), MA and DMA and in blood As(V), MA and DMA.With proper sample preparation and storage of urine (no preservation agents/storage in liquid nitrogen) no analytical artefacts were observed and absence of significant amounts of alleged trivalent metabolites was proven. On the contrary, in blood samples a certain amount of arsenic can get lost in the speciation procedure what was especially noticeable for the blood cells although also plasma/serum gave rise to some disappearance of arsenic. The latter losses may be attributed to precipitation of As(III)-containing proteins/peptides during the methanol/water extraction procedure whereas the former losses were due to loss of specific As(III)-complexing proteins/peptides (e.g. cysteine, metallothionein, reduced GSH, ferritin) on the column (Hamilton PRP-X100) during the separation procedure. Contemporary analytical protocols are not able to completely avoid artefacts due to losses from the sampling to the detection stage so that it is recommended to be careful with the explanation of results, particularly regarding metabolic and pharmacokinetic interpretations, and always aim to compare the sum of species with the total arsenic concentration determined independently.     

Tailored Zwitterionic Hemicyanine Reporters for Early Diagnosis and Prognostic Assessment of Acute Renal Failure

Drug-induced renal failure (DIRF) poses a serious medical complication with high mortality risk. However, early diagnosis or prognosis of DIRF remain challenging, as current methods rely on detecting late-stage biomarkers. Herein we present a library of zwitterionic unimolecular hemicyanines (ZCs) available for constructing activatable reporters to detect DIRF since its initial stage. Zwitterionic properties of these probes are achieved through interspersedly integrating alkyl sulfonates and quaternary ammonium cations onto hemicyanine skeleton, which result in record low plasma protein binding (<5 %) and remarkable renal clearance efficiencies (≈96 %). An activatable reporter ZCRR is further developed by masking the optimal candidate ZC6 with a tetrapeptide specifically cleavable by caspase-8, an initiating indicator of apoptosis. In living mice with cisplatin-induced DIRF, systematically administered ZCRR efficiently accumulates in kidneys and responds to elevated caspase-8 for near-infrared fluorescence signals ‘turn-on’, enabling sensitive detection of intrarenal apoptosis 60 h earlier than clinical methods, and precise evaluation of apoptosis remediation effects by different medications on DIRF mice. As it's urinary excretable, ZCRR also allows for remote detection of DIRF and predicting renoprotective efficacy through in vitro optical urinalysis. This study thus presents unimolecular renal clearable scaffolds that are applicable to developing versatile activatable reporters for renal diseases management.     

Synthesis of nickel cobalt-codoped tin oxide nanoparticles from Psidium guajava with anticancer properties

Metal oxide nanoparticles have been found to selectively target the tumor cells while non-toxic to the normal cells. Leukemia is one of the widespread and deadly cancers in adults, as well as the most common cancer in children. Recently, the nanoparticles have evolved as a simple, economic, effective, and ecologically sound strategy among the known nanoparticle synthesis techniques. In the present study, the structural, optical, and antibacterial effects of nickel cobalt-codoped Tin oxide nanoparticles (SnNiCoO2 NPs) formulated by the green process and the anticancer potential of SnNiCoO2 NPs in Molt-4 cells have been studied. The cytotoxic potential of the NPs against Molt-4 cells was estimated by MTT assay. The ROS and MMP levels were measured using fluorescent dyes and the changes in morphology and nuclei were noted using AO/EB staining. CAT, SOD, MDA, and GSH), and Proinflammatory Cytokines (TNF-α and IL1β) were also studied. The activity of caspase-3, ?9, and ?8 levels was examined to analyze the apoptotic mechanism. The XRD patterns of SnNiCoO2 NPs revealed a tetragonal structure. The SnNiCoO2 NPs was revealed a diameter of 126 nm by the DLS study. The morphology and elemental composition were studied using FESEM and EDAX spectra. In the FT-IR study, the O-sn-O stretching band was found to be 615 and 542 cm-1. The antimicrobial potential of the SnNiCoO2 NPs was examined against S. aureus, E. coli, and C. Albicans strains. A tremendous reduction in the viability of MOLT-4 cells at concentration-dependent mode witnessed the cytotoxic potential of the formulated NPs. The augmented ROS accumulation, depletion of MMP status, depleted antioxidants, and increased proinflammatory cytokines (TNF-α and IL1β) were noted on the NPs exposed cells. Furthermore, the increased expressions of caspase-3, ?9, and ?8 was also noted in the NPs treated MOLT-4 cells. Hence, the outcomes suggest that the formulated SnNiCoO2 NPs had remarkably potent antimicrobial and anticancer properties and could potentially prove beneficial in cancer treatment. Induces mitochondrial oxidative stress with nickel–cobalt-codoped tin oxide nanoparticles from Psidium guajava, which is a potential drug candidate for the antibiotic, antifungal, and anticancer activities of plant-based nanoparticles.     

基于直立碳纳米管大面积金粒子的DNA生物传感器用于早幼粒白血病/维甲酸受体α融合基因检测

基于直立碳纳米管上的大面积金粒子构建了新型的电化学DNA生物传感器,用于急性早幼粒细胞白血病PML/RARα融合基因的检测。首先在直立碳纳米管电极表面溅射金粒子,采用自组装方法将巯基修饰的单链DNA固定到电极上,将氨基修饰的单链DNA和羧基化的CdTe量子点通过酰胺缩合反应生成CdTe修饰的DNA探针,通过与目标DNA的双杂交反应形成三明治结构,利用差分脉冲阳极溶出伏安法检测电极表面捕获的CdTe量子点,从而对DNA进行定量分析。结果表明,电极上Cd2+峰电流与目标DNA浓度(1.0×10-12~1.0×10-8 mol/L)的对数值呈线性关系,线性方程为ipa(μA)=1.626+0.132lgC(mol/L)(R=0.996),检出限为4.0×10-13 mol/L(3σ)。传感器表现出良好的重现性和稳定性。     

急性脑梗死患者脑微出血的发病情况及其危险因素分析

目的探讨急性脑梗死患者脑微出血的发病情况及其危险因素。方法选择急性脑梗死患者75例,男51例,女24例,年龄42～83（64.9±10.8）岁。行头颅CT、磁敏感成像（SWI）检查,依据脑微出血检出的结果分成阳性组（23例）与阴性组（52例）,比较两组的一般资料,探讨脑微出血发病的危险因素。结果SWI检查的检出率比CT检出率高（χ2=27.17,P＜0.05）。阳性组年龄、高血压病、糖尿病患病率均较阴性组高,差异均有统计学意义（均P＜0.05）;两组性别、血脂异常、心房颤动、冠心病、吸烟、饮酒情况比较,差异均无统计学意义（均P＞0.05）。logistic回归分析显示年龄增长、高血压病是脑微出血的独立危险因素（P＜0.05）。结论急性脑梗死患者合并存在脑微出血的比例高,SWI检查是检测脑微出血的敏感方法,年龄大、高血压病与脑微出血的发生密切相关。     

Isotopologous Organotellurium Probes Reveal Dynamic Hypoxia In Vivo with Cellular Resolution

Changes in the oxygenation state of microenvironments within solid tumors are associated with the development of aggressive cancer phenotypes. Factors that influence cellular hypoxia have been characterized; however, methods for measuring the dynamics of oxygenation at a cellular level in vivo have been elusive. We report a series of tellurium‐containing isotopologous probes for cellular hypoxia compatible with mass cytometry (MC)—technology that allows for highly parametric interrogation of single cells based on atomic mass spectrometry. Sequential labeling with the isotopologous probes (SLIP) in pancreatic tumor xenograft models revealed changes in cellular oxygenation over time which correlated with the distance from vasculature, the proliferation of cell populations, and proximity to necrosis. SLIP allows for capture of spatial and temporal dynamics in vivo using enzyme activated probes.     

人血清中cTnI的化学发光酶免疫分析研究——实验条件的优化

采用高效化学发光试剂3-(2'-螺旋金刚烷)-4-甲氧基-4-(3"-羟基)苯-1,2-二氧杂环丁烷磷酸(AMPPD)作为检测底物, 并将传统的ELISA两步双抗夹心法改为一步法, 得到了高灵敏测定人血清中心肌肌钙蛋白I(cTnI)的化学发光酶免疫分析优化条件. 采用单因素变化法和方阵滴定法得到的最佳实验条件为: 捕获抗体包被浓度为10.0 μg/mL, 以pH=7.0的PBS作为免疫反应缓冲底液, 以含质量分数为1.0%的BSA pH=9.6的碳酸盐溶液缓冲液, 于4 ℃封闭过夜, 生物素-检测抗体(Biotin-IgG2)以及碱性磷酸酶-亲和素(ALP-Avidin)结合物均采用1:2000稀释度, 免疫反应条件为37 ℃, 孵育时间60 min, 以去离子水作为洗涤剂, 以1:100稀释的AMPPD作为发光反应底物, 发光反应时间10 min(37 ℃). 检出限为0.02 ng/mL, 比现行ELISA法灵敏度提高一个数量级; 测定周期约75 min, 比两步法ELISA快得多; 线性范围(0.04~36.20 ng/mL)比ELISA法扩宽了两个数量级; 加标回收率97.5%~102.8%, 对标准样品的测定结果与用ELISA法的测定结果吻合; 重复性好, 3个样品批内变异系数均小于8.5%(n=12).