A simple method to estimate the mean number of lipophilic molecules on nanoparticle surfaces by fluorescence measurements.

Measurements of fluorescence intensity of the hydrophobic pyridinium salt (DTPSH) remaining in the organic phase after partition experiments in the DCM/H2O system allowed an approximate method to be developed to estimate the mean number of molecules (N = 942) on the surface of 22.8 nm gold nanoparticles and the separation (1.89 nm) between these organic molecules. This protocol is based on the ability that the organic molecules possess to coat the surface of the nanoparticle, which can migrate from the organic to the aqueous phase as a result of the driving force of the strong binding of sulfur to gold. To validate our estimation, we used a projection of the results obtained by Wales and Ulker to solve the Thomson problem, a mathematicians' challenge, used as a model to calculate the mean distance (1.82 nm) separating particles on the surface, in excellent agreement with the results obtained by our method. The quality of results, the simplicity of calculations, the low fluorescence detection limit, and the inexpensive materials, recommend this procedure for rapid estimates of the mean number of molecules on the surface of nanoparticles.

TEMPO-Attached Pre-fluorescent Probes Based on Pyridinium Fluorophores.

The photophysical behavior of three pyridinium-derived fluorophores, the N-aryl-2,4,6-triphenylpyridinium, the N-aryl-5,6-dihydro-2,4-diphenylbenzo[h]quinolinium and the N-aryl-5,6,8,9-tetrahydro-7-phenyldibenzo[c,h]acridinium perchlorates, was investigated. Comparison of their fluorescence quantum yields led to the preparation of a novel, more sensitive pyridinium-based, TEMPO-attached prefluorescent probe for H-abstraction processes, the N-{4-[4-(N-oxyl-2,2,6,6-tetramethylpiperidinyl)carbonylamino]phenyl}-5,6,8,9-tetrahydro-7-phenyldibenzo[c,h]-acridinium perchlorate.

Controlled Release of the Anticancer Drug Cyclophosphamide from a Superparamagnetic ß-Cyclodextrin Nanosponge by Local Hyperthermia Generated by an Alternating Magnetic Field.

A ß-cyclodextrin (ß-CD) nanosponge (NS) was synthesized using diphenyl carbonate (DPC) as a cross-linker to encapsulate the antitumor drug cyclophosphamide (CYC), thus obtaining the NSs-CYC system. The formulation was then associated with magnetite nanoparticles (MNPs) to develop the MNPs-NSs-CYC ternary system. The formulations mentioned above were characterized to confirm the deposition of the MNPs onto the organic matrix and that the superparamagnetic nature of the MNPs was preserved upon association. The association of the MNPs with the NSs-drug complex was confirmed through field emission scanning electron microscopy, energy dispersive spectroscopy, transmission electron microscopy, X-ray photoelectron spectroscopy, dynamic light scattering, ζ-potential, atomic absorption spectroscopy, X-ray powder diffraction, selected area electron diffraction, and vibrating-sample magnetometer. The superparamagnetic properties of the ternary system allowed the release of CYC by utilizing magnetic hyperthermia upon the exposure of an alternating magnetic field (AMF). The drug release experiments were carried out at different frequencies and intensities of the magnetic field, complying with the "Atkinson-Brezovich criterion". The assays in AMF showed the feasibility of release by controlling hyperthermia of the drug, finding that the most efficient conditions were F = 280 kHz, H = 15 mT, and a concentration of MNPs of 5 mg/mL. CYC release was temperature-dependent, facilitated by local heat generation through magnetic hyperthermia. This phenomenon was confirmed by DFT calculations. Furthermore, the ternary systems outperformed the formulations without MNPs regarding the amount of released drug. The MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) assays demonstrated that including CYC within the magnetic NS cavities reduced the effects on mitochondrial activity compared to those observed with the free drug. Finally, the magnetic hyperthermia assays showed that the tertiary system allows the generation of apoptosis in HeLa cells, demonstrating that the MNPs embedded maintain their properties to generate hyperthermia. These results suggest that using NSs associated with MNPs could be a potential tool for a controlled drug delivery in tumor therapy since the materials are efficient and potentially nontoxic.

Plasmon Chemistry on Ag Nanostars: Experimental and Theoretical Raman/SERS Study of the Pesticide Thiacloprid Bond Cleavage by the Plasmon Deactivation Effect.

Silver nanoparticles (AgNPs) were synthetized and employed in surface-enhanced Raman scattering measurements to study the chemical behavior when thiacloprid (Thia) interacts with the surface of Ag nanospheres (AgNSp) and Ag nanostars (AgNSt) upon excitation of the system with a 785 nm laser. Experimental results show that the deactivation of the localized surface plasmon resonance induces structural changes in Thia. When AgNSp are used, it is possible to observe a mesomeric effect in the cyanamide moiety. On the other hand, when AgNSt are employed, it promotes the cleavage of the methylene (-CH2-) bridge in Thia to produce two molecular fragments. To support these results, theoretical calculations based on topological parameters described by the atoms in molecules theory, Laplacian of the electron density at the bond critical point (∇2ρ BCP), Laplacian bond order, and bond dissociation energies were made, confirming that the bond cleavage is centered at the -CH2- bridge in Thia.

Peptide Targeted Gold Nanoplatform Carrying miR-145 Induces Antitumoral Effects in Ovarian Cancer Cells.

One of the recent attractive therapeutic approaches for cancer treatment is restoring downregulated microRNAs. They play an essential muti-regulatory role in cellular processes such as proliferation, differentiation, survival, apoptosis, cell cycle, angiogenesis, and metastasis, among others. In this study, a gold nanoplatform (GNPF) carrying miR-145, a downregulated microRNA in many cancer types, including epithelial ovarian cancer, was designed and synthesized. For targeting purposes, the GNPF was functionalized with the FSH33 peptide, which provided selectivity for ovarian cancer, and loaded with the miR-145 to obtain the nanosystem GNPF-miR-145. The GNPF-mir-145 was selectively incorporated in A2780 and SKOV3 cells and significantly inhibited cell viability and migration and exhibited proliferative and anchor-independent growth capacities. Moreover, it diminished VEGF release and reduced the spheroid size of ovarian cancer through the damage of cell membranes, thus decreasing cell viability and possibly activating apoptosis. These results provide important advances in developing miR-based therapies using nanoparticles as selective vectors and provide approaches for in vivo evaluation.

ß-Cyclodextrin-Based Nanosponges Inclusion Compounds Associated with Gold Nanorods for Potential NIR-II Drug Delivery.

This article describes the synthesis and characterization of two nanocarriers consisting of ß-cyclodextrin-based nanosponges (NSs) inclusion compounds (ICs) and gold nanorods (AuNRs) for potential near-infrared II (NIR-II) drug-delivery systems. These nanosystems sought to improve the stability of two drugs, namely melphalan (MPH) and curcumin (CUR), and to trigger their photothermal release after a laser irradiation stimulus (1064 nm). The inclusion of MPH and CUR inside each NS was confirmed by field emission scanning electron microscopy (FE-SEM), Raman spectroscopy, Fourier transform infrared spectroscopy, (FT-IR) differential scanning calorimetry (DSC), transmission electron microscopy (TEM), and proton nuclear magnetic resonance (1H-NMR). Furthermore, the association of AuNRs with both ICs was confirmed by FE-SEM, energy-dispersive spectroscopy (EDS), TEM, dynamic light scattering (DLS), ζ-potential, and UV-Vis. Moreover, the irradiation assays demonstrated the feasibility of the controlled-photothermal drug release of both MPH and CUR in the second biological window (1000-1300 nm). Finally, MTS assays depicted that the inclusion of MPH and CUR inside the cavities of NSs reduces the effects on mitochondrial activity, as compared to that observed in the free drugs. Overall, these results suggest the use of NSs associated with AuNRs as a potential technology of controlled drug delivery in tumor therapy, since they are efficient and non-toxic materials.

Ceftriaxone-based Schiff base transition metal(II) complexes. Synthesis, characterization, bacterial toxicity, and DFT calculations. Enhanced antibacterial activity of a novel Zn(II) complex against S. aureus and E. coli.

From the reaction of ceftriaxone 1 antibiotic with 2,6-diaminopyridine 2 a ceftriaxone-based Schiff base (H2L,3) was obtained and its transition metal complexes were synthesized. Spectroscopic and physicochemical techniques, namely, UV-visible, FT-IR, 1H NMR, EPR, mass spectrometry, molar conductance, magnetic susceptibility and density functional theory (DFT) calculations, together with elemental and thermal analyses, were used to find out the binding mode and composition of these complexes. The ceftriaxone-based Schiff base 3 behaves as a monoanionic tridentate N,N,O ligand. Spectral and magnetic data suggest an octahedral geometry for all complexes and the general formulae [M(HL)(OAc)(H2O)2] (M(II) = Mn2+4, Co2+5, Ni2+6, Cu2+7, Zn2+8), are proposed for them. All compounds were screened for antibacterial activity using both the agar disc diffusion method and the minimal inhibitory concentration (MIC). It was found that complex 8 exhibited the most promising bactericidal activity against S. aureus (MIC = 0.0048 µmol/ml) and E. coli (MIC = 0.0024 µmol/ml). It is more active than the free ligand 1 (MIC = 0.0560 µmol/ml for S. aureus and 0.0140 µmol/ml for E. coli). These MIC results were compared with those obtained using similar zinc(II) Schiff base complexes, and with the values obtained using ceftriaxone conjugated with silver and gold nanoparticles (NPs), using earlier published data. Synthesized metal complexes exhibited LC50 values >1000 ppm indicating their nontoxicity against brine shrimp nauplii (Artemia Salina).

Alkylated Benzodithienoquinolizinium Salts as Possible Non-Fullerene Organic N-Type Semiconductors: An Experimental and Theoretical Study.

Three photobicyclized benzodithienoquinolizinium tetrafluoroborates (BPDTQBF4) were prepared and evaluated by UV-Vis and fluorescence spectral, electrochemical analysis, and by theoretical calculations as possible organic n-type semiconductors. Evaluation and comparison of their LUMO levels, HOMO-LUMO energy gaps as monomeric and π-stacked dimers with those of other materials, suggest their potential as organic n-type semiconductors. Calculations of their relative charge carrier mobilities confirmed this potential for one derivative with a long (C-14) alkyl chain appended to the polycyclic planar π-system.

The curvature of gold nanoparticles influences the exposure of amyloid-ß and modulates its aggregation process.

Gold nanoparticles (GNP) are tunable nanomaterials that can be used to develop rational therapeutic inhibitors against the formation of pathological aggregates of proteins. In the case of the pathological aggregation of the amyloid-ß protein (Aß), the shape of the GNP can slow down or accelerate its aggregation kinetics. However, there is a lack of elementary knowledge about how the curvature of GNP alters the interaction with the Aß peptide and how this interaction modifies key molecular steps of fibril formation. In this study, we analysed the effect of flat gold nanoprisms (GNPr) and curved gold nanospheres (GNS) on in vitro Aß42 fibril formation kinetics by using the thioflavin-based kinetic assay and global fitting analysis, with several models of aggregation. Whereas GNPr accelerate the aggregation process and maintain the molecular mechanism of aggregation, GNS slow down this process and modify the molecular mechanism to one of fragmentation/secondary nucleation, with respect to controls. These results can be explained by a differential interaction between the Aß peptide and GNP observed by Raman spectroscopy. While flat GNPr expose key hydrophobic residues involved in the Aß peptide aggregation, curved GNS hide these residues from the solvent. Thus, this study provides mechanistic insights to improve the rational design of GNP nanomaterials for biomedical applications in the field of amyloid-related aggregation.

Adsorption of bovine serum albumin on gold nanoprisms: interaction and effect of NIR irradiation on protein corona.

Because of their photothermal properties, gold nanoparticles (AuNPs) have gained attention regarding their use in drug delivery and therapeutic applications. In this sense, it is interesting to consider their interactions with biologically available proteins, such as serum albumin, as well as the effects of irradiation and photothermal conversion on the protein structure that can lead to a loss of function or generate an immune response. Gold nanoprisms (AuNPrs) have gained interest due to their low toxicity, ease of synthesis, and excellent stability, promoting their use in bioapplications such as surface-enhanced Raman spectroscopy (SERS), drug delivery, and photothermal therapy. The interaction between AuNPrs, with plasmon bands centred in the near-infrared region (NIR), and bovine serum albumin (BSA) has not been explored yet. UV-Vis spectroscopy, dynamic light scattering (DLS) and fluorescence spectroscopy were used to study the interaction between AuNPrs and BSA in addition to estimation of the adsorption rate and kinetic and thermodynamic parameters (K, ΔH°, ΔG°, ΔS°, and Ea) using adsorption isotherms and Langmuir and Freundlich models. The results suggest spontaneous cooperative binding in multilayer adsorption, achieved by the chemisorption of BSA on the AuNPr surface through the S-Au interaction, as confirmed by Raman spectroscopy. On the other hand, the photothermal conversion efficiency (PE) of the coated nanoparticles after NIR irradiation was assessed, resulting in a slight decrease in the PE of BSA coated on AuNPrs in comparison with that of noncapped nanoparticles. The effect of the irradiation on the protein conformation of capped nanoparticles was also assessed; circular dichroism showed BSA unfolding upon interaction with AuNPrs, with a decrease in the α-helix and ß-sheet contents, as well as an increase in random coil conformations. Changes in the Raman spectrum suggest a modification of the disposition of the protein residues exposed to the gold surface after NIR irradiation; but at the secondary structure level, no relevant changes were observed. This provides possibilities for the use of NPs-BSA for bioapplications based on the photothermal effect promoted by laser irradiation, since the biological identity of the protein is preserved after NIR irradiation.

Intranasal administration of gold nanoparticles designed to target the central nervous system: Fabrication and comparison between nanospheres and nanoprisms.

The presence of the blood-brain barrier (BBB) limit gold nanoparticles (GNP) accumulation in central nervous system (CNS) after intravenous (IV) administration. The intranasal (IN) route has been suggested as a good strategy for circumventing the BBB. In this report, we used gold nanoprisms (78 nm) and nanospheres (47 nm), of comparable surface areas (8000 vs 7235 nm2) functionalized with a polyethylene glycol (PEG) and D1 peptide (GNPr-D1 and GNS-D1, respectively) to evaluate their delivery to the CNS after IN administration. Cell viability assay showed that GNPr-D1 and GNS-D1 were not cytotoxic at concentrations ranged between 0.05 and 0.5 nM. IN administration of GNPr-D1 and GNS-D1 demonstrated a significant difference between the two types of GNP, in which the latter reached the CNS in higher levels. Pharmacokinetic study showed that the peak brain level of gold was 0.75 h after IN administration of GNS-D1. After IN and IV administrations of GNS-D1, gold concentrations found in brain were 55 times higher via the IN route compared to IV administration. Data revealed that the IN route is more effective for targeting gold to the brain than IV administration. Finally, no significant difference was observed between the IN and IV routes in the distribution of GNS-D1 in the various brain areas.

Gold Nanoparticles Mediate Improved Detection of ß-amyloid Aggregates by Fluorescence.

The early detection of the amyloid beta peptide aggregates involved in Alzheimer's disease is crucial to test new potential treatments. In this research, we improved the detection of amyloid beta peptide aggregates in vitro and ex vivo by fluorescence combining the use of CRANAD-2 and gold nanorods (GNRs) by the surface enhancement fluorescence effect. We synthetized GNRs and modified their surface with HS-PEG-OMe and HS-PEG-COOH and functionalized them with the D1 peptide, which has the capability to selectively bind to amyloid beta peptide. For an in vitro detection of amyloid beta peptide, we co-incubated amyloid beta peptide aggregates with the probe CRANAD-2 and GNR-PEG-D1 observing an increase in the intensity of the fluorescence signal attributed to surface enhancement fluorescence. Furthermore, the surface enhancement fluorescence effect was observed in brain slices of transgenic mice with Alzheimer´s disease co-incubated with CRANAD-2 and GNR-PEG-D1. An increase in the fluorescence signal was observed allowing the detection of aggregates that cannot be detected with the single use of CRANAD-2. Gold nanoparticles allowed an improvement in the detection of the amyloid aggregated by fluorescence in vitro and ex vivo.

Theoretical surface-enhanced Raman spectra study of substituted benzenes I. Density functional theoretical SERS modelling of benzene and benzonitrile.

This paper reports a DFT modelling of SERS spectra for benzene and benzonitrile on the basis of a simple noncoordinate substrate-adsorbate model. Assignment of normal modes was obtained from internal force constants and potential energy distribution matrices and used to identify, according the SERS selection rules, the orientation of the optimized molecules on the metallic surface. Calculated band enhancements are in good agreement with experimental observations. The optimized geometry parameters of the molecule-Ag system, changes of HOMO-LUMO energies are discussed to give insight in the different SERS mechanisms for both molecules.

Theoretical surface-enhanced Raman spectra study of substituted benzenes II. Density functional theoretical SERS modelling of o-, m-, and p-methoxybenzonitrile.

The SERS modelling of o-, m-, and p-methoxybenzonitrile has been performed following the same methodology that in Part I. Optimized structure obtained from DFT calculations in a B3LYP-LANL2DZ level of calculation shows different tilted positions for the isomers under study. From correlations obtained by comparison of Raman and SERS spectra concerning geometrical parameters, frequency shifting, change in band intensity, and force constants is possible to give insight about the different effect of the metal surface on these molecules and the structural reasons of this behaviour. Frontier orbital analysis gives further information and reveals a ligand to metal charge transfer mechanism for all isomers, as well as its relative importance.

Exploring the influence of Diels-Alder linker length on photothermal molecule release from gold nanorods.

We studied the photothermal release of carboxyfluorescein (CF) linked to the gold surface of gold nanorods (GNRs) by two Diels-Alder adducts of different lengths (n = 4 and n = 9). The functionalized GNRs were irradiated with infrared light to produce photothermal release of CF by a retro-Diels-Alder reaction. The adducts were chemisorbed on the GNRs and the functionalized nanoparticles were characterized by UV-vis, DLS, zeta potential and Raman and surface-enhanced Raman spectroscopy (SERS). On the basis of the degree of nanoparticle functionalization and the SERS results, we inferred the orientation of CF on the surface of the gold nanoparticle. Moreover, we determined the photothermal release profiles of CF from the gold surface by laser irradiation. The release was faster for the longer linker (n = 9). SERS revealed that, for the shorter linker (n = 4), molecules are oriented perpendicularly with respect to the gold surface, thereby maintaining the CF far from the surface. In contrast, the longer linker was observed to be tilted, thus maintaining CF close to the gold surface and therefore potentially favoring the photothermal transfer of energy. These results are relevant for the future development of the spatial and temporal controlled release of drugs by means of gold nanoparticles.

Vibrational and scaled quantum chemical study of O,O-dimethyl S-methylcarbamoylmethyl phosphorodithioate, dimethoate.

Infrared and Raman spectra of O,O-dimethyl S-methylcarbamoylmethylphosphorodithioate, dimethoate, have been recorded. Density functional theory, DFT, with the B3LYP functional was used for the optimization of the ground state geometry and simulation of the infrared and Raman spectra of this molecule. Calculated geometrical parameters fit very well with the experimental ones. Based on the recorded data, the DFT results and a normal coordinate analysis based on a scaled quantum mechanical (SQM) force field approach, a complete vibrational assignment was made for the first time.

Impacto de un modelo de gestión de enfermedad en una población con tratamiento de diálisis en Colombia / Impact of a disease management model on a population undergoing dialysis in Colombia

Resumen Introducción. La implementación de modelos de gestión de enfermedad (MGE) ha demostrado mejores desenlaces en salud. Objetivo. Describir la tasa de hospitalización y mortalidad en una cohorte de pacientes con tratamiento de diálisis en la que se implementó un MGE. Materiales y métodos. Estudio de cohorte prospectivo en el que se incluyeron pacientes prevalentes en diálisis, mayores de 18 años, pertenecientes a la entidad promotora de salud del régimen contributivo Nueva EPS y con al menos tres meses de intervención con MGE en la red Renal Therapy Services (RTS) entre el 1 de enero y el 31 de diciembre de 2014. Para el análisis se usaron modelos multivariables de supervivencia y estadística descriptiva. Resultados. Se evaluaron 2 525 pacientes; la mediana de edad fue 64.5 años (RIC=19), el 56.9% (n=1 437) estaban en hemodiálisis, el 59.5% (n=1 503) fueron hombres y se encontró una tasa de hospitalización de 1.15 eventos por paciente/año (IC95%: 1.10-1.19) con 9.6 días hospitalarios paciente/año. La tasa de mortalidad fue de 146 muertes por 1 000 pacientes/año (IC95%: 130.3-163.6). Conclusión. A pesar de la alta comorbilidad observada en esta población en diálisis intervenida con un MGE, se encontraron desenlaces clínicos favorables.

Abstract Introduction: The implementation of disease management models (DMM) has shown better health outcomes. Objective: To describe hospitalization and mortality rates in a cohort of patients on dialysis in which a DMM was implemented. Materials and methods: Prospective cohort study in which prevalent dialysis patients, older than 18 years of age, belonging to the health promoter of the contributory scheme (Nueva EPS), and with at least three months of intervention with DMM, were included in the Renal Therapy Services Network (RTS) between January 1 and December 31, 2014.To conduct the multivariate analysis, survival models and descriptive statistics were used. Results: 2 525 patients were evaluated; median age was 64.5 years (IR=19); 56.9% (n=1 437) were on hemodialysis; 59.5% (n=1,503) were male, and a hospitalization rate of 1.15 events per patient/year was found (95% CI: 1.10-1.19) with 9.6 hospital patient days/year. The mortality rate was 146 deaths per 1 000 patients/year (95% CI: 130.3-163.6). Conclusion: Despite the high comorbidity observed in the population undergoing dialysis managed with DMM, favorable clinical outcomes were found.