Luminescent lanthanide(III) complexes of DTPA-bis(amido-phenyl-terpyridine) for bioimaging and phototherapeutic applications.

We report here a series of coordinatively-saturated and thermodynamically stable luminescent [Ln(dtntp)(H2O)] [Ln(III) = Eu (1), Tb (2), Gd (3), Sm (4) and Dy (5)] complexes using an aminophenyl-terpyridine appended-DTPA (dtntp) chelating ligand as cell imaging and photocytotoxic agents. The N,N″-bisamide derivative of H5DTPA named as dtntp is based on 4'-(4-aminophenyl)-2,2':6',2″-terpyridine conjugated to diethylenetriamine-N,N',N″-pentaacetic acid. The structure, physicochemical properties, detailed photophysical aspects, interaction with DNA and serum proteins, and photocytotoxicity were studied. The intrinsic luminescence of Eu(III) and Tb(III) complexes due to f â†’ f transitions used to evaluate their cellular uptake and distribution in cancer cells. The solid-state structure of [Eu(dtntp)(DMF)] (1·DMF) shows a discrete mononuclear molecule with nine-coordinated {EuN3O6} distorted tricapped-trigonal prism (TTP) coordination geometry around the Eu(III). The {EuN3O6} core results from three nitrogen atoms and three carboxylate oxygen atoms, and two carbonyl oxygen atoms of the amide groups of dtntp ligand. The ninth coordination site is occupied by an oxygen atom of DMF as a solvent from crystallization. The designed probes have two aromatic pendant phenyl-terpyridine (Ph-tpy) moieties as photo-sensitizing antennae to impart the desirable optical properties for cellular imaging and photocytotoxicity. The photostability, coordinative saturation, and energetically rightly poised triplet states of dtntp ligand allow the efficient energy transfer (ET) from Ph-tpy to the emissive excited states of the Eu(III)/Tb(III), makes them luminescent cellular imaging probes. The Ln(III) complexes show significant binding tendency to DNA (K ~ 104 M-1), and serum proteins (BSA and HSA) (K ~ 105 M-1). The luminescent Eu(III) (1) and Tb(III) (2) complexes were utilized for cellular internalization and cytotoxicity studies due to their optimal photophysical properties. The cellular uptake studies using fluorescence imaging displayed intracellular (cytosolic and nuclear) localization in cancer cells. The complexes 1 and 2 displayed significant photocytotoxicity in HeLa cells. These results offer a modular design strategy with further scope to utilize appended N,N,N-donor tpy moiety for developing light-responsive luminescent Ln(III) bioprobes for theranostic applications.

Modulation of ruthenium anticancer drugs analogs with tolfenamic acid: Reactivity, biological interactions and growth inhibition of yeast cell.

We synthesized two ruthenium(II) complexes: trans,trans-[Ru(im)2(tfa)2] (1) and trans,trans­[Ru(in)2(tfa)2] (2) where im = 1H­imidazole, in = 1H­indazole and tfa = tolfenamic acid, a potential nonsteroidal anti-inflammatory drug (NSAID). The NSAID was opted as bioactive ligand to understand its synergistic therapeutic effect in structurally analogous Ru(II)-compounds with KP418 (imidazolium trans­[tetrachloridobis(1H­imidazole)ruthenate(III)]) and KP1019 (indazolium trans­[tetrachloridobis(1H­indazole)ruthenate(III)]). The complexes were studied using various analytical methods and structure was determined by X-ray crystallography. Both the complexes display discrete mononuclear Ru(II) center in {RuN4O2} distorted octahedral geometry. The reactivity of the complexes was tested with potentially important biomolecules involved in metabolism of cancer cells, viz. l­arginine, dl­methionine, glutathione and L(+)ascorbate. Such studies intended to provide deeper insights on intracellular speciation and kinetic substitution encountered by Ru-drugs to target alternative cell death pathways. The complexes demonstrate a preferential binding affinity with calf thymus DNA (Kb ~ 104 M-1) and human serum albumin (KHSA = 105 M-1). Both the complexes showed potent inhibition of wild type yeast cell growth in a dose-dependent manner. Yeast cells were used as a powerful model system to study the molecular mechanism of pathobiology which shares a high degree of conservation of both cellular and molecular processes with human cells for assessing toxicity potential of the complexes. Fluorescence imaging studies reveal the localization of both complexes to yeast mitochondria despite its rigid cell wall and induce mitochondrial damage and formation of reactive oxygen species (ROS). The Micrococcal nuclease assay revealed complexes do not alter global nucleosome occupancy and probably target specific regions of the genome.

Near-infrared excited cooperative upconversion in luminescent Ytterbium(ΙΙΙ) bioprobes as light-responsive theranostic agents.

Near-infrared (NIR) Ytterbium(ΙΙΙ) complexes namely [Yb(dpq)(DMF)2Cl3] (1), [Yb(dppz)(DMF)2Cl3] (2), [Yb(dpq)(ttfa)3] (3) and [Yb(dppz)(ttfa)3] (4) based on photosensitizing antenna: dipyrido-[3,2-d:2',3'-f]-quinoxaline (dpq), dipyrido-[3,2-a:2',3'-c]-phenazine (dppz) and 4,4,4-trifluoro-1-(2-thienyl)-1,3-butanedione (Httfa), were designed as NIR bioimaging agents utilizing cooperative upconversion luminescence (CUCL) of Yb(III). Their structures, detailed photophysical properties, biological interactions, photo-induced DNA cleavage, NIR photocytotoxicity and cellular internalization and bioimaging properties were examined. Discrete mononuclear complexes adopt a seven-coordinated {LnN2O2Cl3} mono-capped octahedron (1, 2) and eight-coordinated {LnN2O6} distorted square antiprism geometry (3, 4) with bidentate N, N-donor dpq, dppz and O,O-donor ttfa ligands. The designed Yb(III) probes (3, 4) having advantages of dual sensitizing antennae (dpq/dppz and Httfa) to modulate the desirable optical properties in NIR region for bioimaging in biologically transparent window and light-responsive intracellular damage with spatiotemporal control. The lack of inner-sphere water (q = 0), remarkable photostability, large Stokes' shifts, presence of energetically rightly poised ligand 3T states allows efficient energy transfer (ET) to the emissive 2F5/2 state of Yb(ΙΙΙ). The unique cooperative upconversion luminescence (CUCL) of Yb(III) was observed in 1-4 in the visible blue region (λem = 490 nm) upon NIR excitation at 980 nm, makes them special candidates for NIR-to-visible or NIR-to-NIR cellular imaging probes. The CUCL property of Yb(III) were observed in the discrete mononuclear complexes both in solid state and solution. We elegantly utilized this remarkable property of Yb(III) for cellular imaging application for the first time to the our knowledge including potential uses in CUC/multiphoton excitation microscopy. The complexes exhibit significant binding propensity to DNA, HSA and BSA (K ∼ 105 M-1). They effectively cleave supercoiled (SC) DNA to its nicked circular (NC) form at 365 nm via photoredox pathways. The cellular uptake studies evidently displayed cytosolic and nuclear localization of the complexes. Finally, the capability of Yb(III) complexes usage for PDT were demonstrated through significant near-IR photocytotoxicity at 980 nm CW laser. The results depicted here offers an intelligent strategy towards developing light-responsive highly photostable Yb(III) probes for NIR theranostic application in the biologically transparent phototherapeutic window.

Ruthenium(II) complexes of saccharin with dipyridoquinoxaline and dipyridophenazine: Structures, biological interactions and photoinduced DNA damage activity.

Ruthenium complexes trans-[Ru(sac)2(dpq)2] (1) and trans-[Ru(sac)2(dppz)2] (2) where sac is artificial sweetener saccharin (o-sulfobenzimide; 1,2-benzothiazole-3(2H)-one1,1-dioxide (Hsac)), dpq = dipyrido[3,2-d:2',3'-f]quinoxaline and dppz = dipyrido[3,2-a:2',3'-c]phenazine have been synthesized and thoroughly characterized using various analytical and spectral techniques. Saccharin known to act as carbonic anhydrase IX (CA IX) inhibitor which is a biomarker for highly aggressive and proliferative tumor in hypoxic stress, so inhibition of CA IX is a potential strategy for anticancer chemotherapy. The solid state structures, photophysical properties, photostability, DNA and protein binding affinity, and DNA photocleavage activity were explored. The structural analysis revealed Ru(II) centre is in discrete mononuclear, distorted octahedral {RuN6} coordination geometry with two monoanionic nitrogen donor saccharinate ligands and two neutral bidentate nitrogen donors ligands dpq and dppz. cis-[Ru(sac)2(dppz)2] (cis-2) geometrical isomer was also isolated and structurally characterized by X-ray crystallography. The photo-induced dissociation of monodentate saccharin ligand is observed when irradiated at UV-A light of 365 nm. The complexes show significant binding affinity to the calf thymus DNA (Kb âˆ¼ 105 M-1) through significant intercalation through planar dpq and dppz ligands. Interaction of complexes 1 and 2 with bovine serum albumin (BSA) showed remarkable tryptophan emission quenching (KBSA ∼105 M-1). The complexes showed appreciable photoinduced DNA cleavage activity upon irradiation of low power UV-A light of 365 nm from supercoiled (SC) to its nicked circular (NC) form at micromolar complex concentrations. Photocleavage mechanistic studies in presence of O2 reveals involvement of reactive oxygen species (ROS) mediated through ligand-centered 3ππ* and/or 3MLCT excited states generated upon photoactivation leads to nicking of supercoiled DNA to nicked circular form. In absence of O2, we also observed photocleavage of DNA through formation of photoinduced ligand dissociated Ru-DNA complex involving PACT pathway.

Dual-Sensitized Luminescent Europium(ΙΙΙ) and Terbium(ΙΙΙ) Complexes as Bioimaging and Light-Responsive Therapeutic Agents.

Dual-photosensitized stable EuΙΙΙ and TbΙΙΙ complexes, namely [Eu(dpq)(tfnb)3 ] (1) and [Tb(dpq)(tfnb)3 ] (2), in which dpq=dipyrido[3,2-d:2',3'-f]quinoxaline and Htfnb=4,4,4-trifluoro-1-(2-napthyl)-1,3-butanedione, were designed as bioimaging and light-responsive therapeutic agents. Their X-ray structures, photophysical properties, biological interactions, photoinduced DNA damage, photocytotoxicity, and cellular uptake properties were studied. Discrete mononuclear complexes adopt an eight-coordinated {LnN2 O6 } distorted square antiprism geometry with bidentate N,N-donor dpq and O,O-donor tfnb ligands. The designed probes have the advantage of dual-sensitizing antennae (dpq, Htfnb) to modulate their desirable optical properties for cellular imaging and light-responsive intracellular damage. The remarkable photostability, absence of inner-sphere water (q<1), and longer excited-state lifetimes of the complexes make them suitable as cellular-imaging probes. The dpq 3 T state is well located energetically to allow efficient energy transfer (ET) to the emissive 5 D0 and 5 D4 states of EuΙΙΙ and TbΙΙΙ . This leads to higher quantum yields (φ=0.15-0.20) in aqueous media and makes these compounds suitable cellular-imaging probes. The complexes display significant binding ability toward DNA and bovine serum albumin (K≈105 m-1 ). They effectively cleave supercoiled DNA to its nicked circular form at λ=365 nm through photoredox pathways. The cellular internalization studies showed cytosolic and nuclear localization. The remarkable photocytotoxicity of these probes offers a strategy towards developing photoresponsive LnΙΙΙ probes as cellular-imaging and phototherapeutic agents.

Simultaneous Detection of Genetically Modified Organisms in a Mixture by Multiplex PCR-Chip Capillary Electrophoresis.

An efficient PCR-based method to trace genetically modified food and feed products is in demand due to regulatory requirements and contaminant issues in India. However, post-PCR detection with conventional methods has limited sensitivity in amplicon separation that is crucial in multiplexing. The study aimed to develop a sensitive post-PCR detection method by using PCR-chip capillary electrophoresis (PCR-CCE) to detect and identify specific genetically modified organisms in their genomic DNA mixture by targeting event-specific nucleotide sequences. Using the PCR-CCE approach, novel multiplex methods were developed to detect MON531 cotton, EH 92-527-1 potato, Bt176 maize, GT73 canola, or GA21 maize simultaneously when their genomic DNAs in mixtures were amplified using their primer mixture. The repeatability RSD (RSDr) of the peak migration time was 0.06 and 3.88% for the MON531 and Bt176, respectively. The RSD (RSDR) of the Cry1Ac peak ranged from 0.12 to 0.40% in multiplex methods. The method was sensitive in resolving amplicon of size difference up to 4 bp. The PCR-CCE method is suitable to detect multiple genetically modified events in a composite DNA sample by tagging their event specific sequences.

Luminescent europium and terbium complexes of dipyridoquinoxaline and dipyridophenazine ligands as photosensitizing antennae: structures and biological perspectives.

The europium(III) and terbium(III) complexes, namely [Eu(dpq)(DMF)2(NO3)3] (1), [Eu(dppz)2(NO3)3] (2), [Tb(dpq)(DMF)2Cl3] (3), and [Tb(dppz)(DMF)2Cl3] (4), where dipyrido[3,2-d:2',3'-f]quinoxaline (dpq in 1 and 3), dipyrido[3,2-a:2',3'-c]phenazine (dppz in 2 and 4) and N,N'-dimethylformamide (DMF) have been isolated, characterized from their physicochemical data, luminescence studies and their interaction with DNA, serum albumin protein and photo-induced DNA cleavage activity are studied. The X-ray crystal structures of complexes 1-4 show discrete mononuclear Ln(3+)-based structures. The Eu(3+) in [Eu(dpq)(DMF)2(NO3)3] (1) and [Eu(dppz)2(NO3)3] (2) as [Eu(dppz)2(NO3)3]·dppz (2a) adopts a ten-coordinated bicapped dodecahedron structure with a bidentate N,N-donor dpq ligand, two DMF and three NO3(-) anions in 1 and two bidentate N,N-donor dppz ligands and three NO3(-) anions in 2. Complexes 3 and 4 show a seven-coordinated mono-capped octahedron structure where Tb(3+) contains bidentate dpq/dppz ligands, two DMF and three Cl(-) anions. The complexes are highly luminescent in nature indicating efficient photo-excited energy transfer from the dpq/dppz antenna to Ln(3+) to generate long-lived emissive excited states for characteristic f → f transitions. The time-resolved luminescence spectra of complexes 1-4 show typical narrow emission bands attributed to the (5)D0 → (7)F(J) and (5)D4 → (7)F(J) f-f transitions of Eu(3+) and Tb(3+) ions respectively. The number of inner-sphere water molecules (q) was determined from luminescence lifetime measurements in H2O and D2O confirming ligand-exchange reactions with water in solution. The complexes display significant binding propensity to the CT-DNA giving binding constant values in the range of 1.0 × 10(4)-6.1 × 10(4) M(-1) in the order 2, 4 (dppz) > 1, 3 (dpq). DNA binding data suggest DNA groove binding with the partial intercalation nature of the complexes. All the complexes also show binding propensity (K(BSA) ∼ 10(5) M(-1)) to the bovine serum albumin (BSA) protein. The intensity of the time-gated luminescence spectral bands enhances significantly with the increasing DNA concentration in aqueous buffer medium due to displacement of bound water upon interaction with DNA, thus reducing non-radiative quenching through the O-H oscillator. Complexes 1-4 efficiently cleave supercoiled (SC) ds-DNA to its nicked circular (NC) form on exposure to UV-A light of 365 nm via formation of singlet oxygen ((1)O2) and hydroxyl radicals (HO˙) as the reactive oxygen species at micromolar concentrations under physiological conditions.

Health conditions among women with a disability.

BACKGROUND: This study was designed to determine if the incidence of some common health conditions was higher among 770 women with a disability compared with 1097 women without a disability and 679 men with a disability in the same primary care medical practices. METHODS: This is a retrospective cohort study that used record review of individuals with sensory impairments (n = 117), developmental disabilities (n = 692), trauma-related impairments (n = 155), and psychiatric impairments (n = 485) and 1097 patients without a disability. RESULTS: Diabetes, hypertension, and obesity, three important predictors of morbidity and mortality, were not significantly more likely to occur in women with disabilities compared with others in the same medical practice. Dementia had higher hazard ratios (HRs) for women with sensory, developmental, and trauma disability. However, women with trauma disability had a significantly lower (HR) for dementia compared with men with the same disability. Women with sensory disability were at higher risk for transient ischemic attack (TIA) compared with women in the same practice without disability, and there was no difference in HRs compared with men with disability. Women with disability related to trauma were at higher risk for depression compared with women in the same practice without disability and compared with men with the same disability. Some conditions, such as congestive heart failure (CHF) and chronic obstructive pulmonary disease (COPD), have opportunities for prevention, as they are associated with smoking, physical inactivity, and diet. CONCLUSIONS: Healthcare providers should be aware of risks associated with specific impairment groups so they can implement prevention and treatment strategies.

Variation in health conditions among groups of adults with disabilities in primary care.

The literature on the health of adults with disabilities focuses on one disability compared to a comparison group. This study allows cross disability comparisons with the hypothesis. Adults with disabilities had higher odds of having common health conditions, compared to adults without disability in the same practice. A retrospective record review of 1449 patients with disability and 2084 patients without disability included individuals with sensory impairments (n = 117), developmental disabilities (n = 692), trauma-related impairments (n = 155) and psychiatric impairments (n = 485). The only two health conditions with statistically significantly increased odds for all groups with disabilities were dementia and epilepsy. Patients with developmental disabilities were less likely to have coronary artery disease, cancer, and obesity. Those with sensory impairments had increased odds for congestive heart failure, diabetes, transient ischemic attacks and death. Patients with trauma disabilities had increased odds for chronic obstructive pulmonary disease, and depression. Finally, psychiatric patients had increased odds for most of the investigated condition. In conclusion, there were many similarities in the risk for common health conditions such as asthma, cancer, coronary artery disease, depression, hypertension, and obesity, among patients with and without disability. Some of the conditions with increased odds ratios, including depression, seizures, and dementia are secondary to the primary disability.

Heart disease, schizophrenia, and affective psychoses: epidemiology of risk in primary care.

A retrospective cohort design was used to study risk factors and cardiovascular end points among adults, with and without psychoses, receiving primary care. Earlier onset of risk factors and heart disease was noted among individuals with schizophrenia compared to those with affective psychoses and no disabilities. Patients with schizophrenia had increased relative risk for obesity, congestive heart failure, dementia, depression and death, while patients with affective psychoses had increased risk for dementia and diabetes.

Obesity among people with and without mental retardation across adulthood.

OBJECTIVE: This study was designed to explore obesity during adulthood and the likelihood of moving out of obesity among 1809 adults without disability and 680 adults with mental retardation who received care at the same primary care practices during the period of 1990 to 2003. RESEARCH METHOD AND PROCEDURES: A retrospective observational design using medical records first identified patients with mental retardation (MR) and age-matched controls without disabilities. Data on BMI collected during each primary care visit allowed exploration of obesity at three levels. Moving out of obesity was defined as having a BMI <25 kg/m(2). We also abstracted data on age, sex, race, and other medical conditions. RESULTS: For adults 20 to 29 years of age, 33.1% of patients without disability and 21% of patients with MR had a BMI >30 kg/m(2). Between the ages of 50 and 59 years, 40.5% of the patients without disability and 35.2% of the patients with MR had a BMI >30 kg/m(2). Patients with mild MR had similar prevalence rates of obesity and patients with severe MR had significantly lower prevalence of obesity compared with the patients without disability through 50 years of age. Throughout the period from 20 to 60 years of age, between 15% and 40% of individuals with and without MR, who were previously obese, were not currently obese. DISCUSSION: Throughout the adult years, an increasing proportion of individuals with and without MR are obese. However, obesity is not a chronic state; many people transition back to a normal body weight.

Depression in adults with disabilities, in primary care.

PURPOSE: This research was design to answer the question: Does the prevalence of depression differ between adults with and without disability, in the same family medicine practice? METHOD: A retrospective cohort design was used, to study depression among adults, with and without primary disabling conditions, receiving primary care in either a university based urban or rural family practice setting. RESULTS: When we compared individuals with disability to those without disability, and controlled for individual characteristics, the relative risk for depression was significantly lower for individuals with autism (Relative Risk (RR) 0.20: 95% Confidence Interval (CI) 0.05-0.55), cerebral palsy with mental retardation (RR 0.40: 95% CI: 0.24-0.65), and MR (RR 0.56: 95% CI: 0.39-0.77). The risk for depression was significantly higher for those with cerebral vascular accidents/stroke (RR 2.18: 95% CI: 1.72-3.76) and traumatic brain injury (RR 2.55: 95% CI: 1.72-2.77). The earliest onset of depression was among individuals with traumatic disabilities and milt mental retardation. Our estimate of depression prevalence for the non-disabled and disabled primary care patients was 22.8% and 24.9% respectively, when patients with disabilities were grouped together (p = 0.008). CONCLUSION: It is important for physicians to recognize the higher prevalence of depression among patients with adult onset disabilities (e.g. stroke, traumatic brain injury). In addition, they should be aware of lower prevalence of depression among many individuals with lifelong disabilities, such as mental retardation, cerebral palsy, and autism.

Prevalence of epilepsy in adults with mental retardation and related disabilities in primary care.

Two primary care practices were used to recruit adults with and without disability. Disability groups included autism, Down syndrome, cerebral palsy, and mental retardation. The patients without disability had an epilepsy prevalence rate of 1%. The prevalence of epilepsy within the disability groups was 13% for cerebral palsy, 13.6% for Down syndrome; 25.4% for autism, 25.5% for mental retardation, and 40% for adults with both cerebral palsy and mental retardation. During the decades of adulthood, the prevalence of epilepsy declined for those with cerebral palsy and mental retardation. The prevalence of epilepsy increased with advancing years for adults with Down syndrome, autism, and those without disability. Nonetheless, during each decade the prevalence of epilepsy was higher in all of the disability groups compared to those without disability.