Magnetic Micellar Nanovehicles: Prospects of Multifunctional Hybrid Systems for Precision Theranostics.

Hybrid nanoarchitectures such as magnetic polymeric micelles (MPMs) are among the most promising nanotechnology-enabled materials for biomedical applications combining the benefits of polymeric micelles and magnetic nanoparticles within a single bioinstructive system. MPMs are formed by the self-assembly of polymer amphiphiles above the critical micelle concentration, generating a colloidal structure with a hydrophobic core and a hydrophilic shell incorporating magnetic particles (MNPs) in one of the segments. MPMs have been investigated most prominently as contrast agents for magnetic resonance imaging (MRI), as heat generators in hyperthermia treatments, and as magnetic-susceptible nanocarriers for the delivery and release of therapeutic agents. The versatility of MPMs constitutes a powerful route to ultrasensitive, precise, and multifunctional diagnostic and therapeutic vehicles for the treatment of a wide range of pathologies. Although MPMs have been significantly explored for MRI and cancer therapy, MPMs are multipurpose functional units, widening their applicability into less expected fields of research such as bioengineering and regenerative medicine. Herein, we aim to review published reports of the last five years about MPMs concerning their structure and fabrication methods as well as their current and foreseen expectations for advanced biomedical applications.

Controlling Macrophage Polarization to Modulate Inflammatory Cues Using Immune-Switch Nanoparticles.

The persistence of inflammatory mediators in tissue niches significantly impacts regenerative outcomes and contributes to chronic diseases. Interleukin-4 (IL4) boosts pro-healing phenotypes in macrophages (Mφ) and triggers the activation of signal transducer and activator of transcription 6 (STAT6). Since the IL4/STAT6 pathway reduces Mφ responsiveness to inflammation in a targeted and precise manner, IL4 delivery offers personalized possibilities to overcome inflammatory events. Despite its therapeutic potential, the limited success of IL4-targeted delivery is hampered by inefficient vehicles. Magnetically assisted technologies offer precise and tunable nanodevices for the delivery of cytokines by combining contactless modulation, high tissue penetration, imaging features, and low interference with the biological environment. Although superparamagnetic iron oxide nanoparticles (SPION) have shown clinical applicability in imaging, SPION-based approaches have rarely been explored for targeted delivery and cell programming. Herein, we hypothesized that SPION-based carriers assist in efficient IL4 delivery to Mφ, favoring a pro-regenerative phenotype (M2φ). Our results confirmed the efficiency of SPION-IL4 and Mφ responsiveness to SPION-IL4 with evidence of STAT6-mediated polarization. SPION-IL4-treated Mφ showed increased expression of M2φ associated-mediators (IL10, ARG1, CCL2, IL1Ra) when compared to the well-established soluble IL4. The ability of SPION-IL4 to direct Mφ polarization using sophisticated magnetic nanotools is valuable for resolving inflammation and assisting innovative strategies for chronic inflammatory conditions.

A theoretical study of the UV absorption of 4-methylbenzylidene camphor: from the UVB to the UVA region.

In this study, a theoretical approach was used to study the UV absorption of the UVB filter, 4-methylbenzylidene camphor. The main objective of this work was to design new UVA filters based on this rather photo-stable compound, so that photo-degradation in this UV region can be avoided without the use of other molecules. This objective was achieved by the simultaneous addition of two appropriate substituents, which led to red-shifts of up to 0.69 eV while maintaining appreciable oscillator strength. Also, useful structure-energy relationships were derived, which allow for the development of more UVA filters based on 4-methylbenzylidene camphor.

Degradation in chlorinated water of the UV filter 4-tert-butyl-4'-methoxydibenzoylmethane present in commercial sunscreens.

4-tert-Butyl-4'-methoxydibenzoylmethane (BMDM) is a widely used ultraviolet A filter. In this work, we have studied the effect of chlorine and dissolved organic matter (DOM) concentrations on the stability of UV filter (BMDM) present in two commercial sunscreen cream formulations in water. An experimental design was used to assess the effect of the two experimental factors on the degradation of BMDM. Higher concentrations of chlorine lead to higher degradation percentages of BMDM and higher concentrations of DOM inhibit its degradation. Moreover, a mono and a dichloro derivate of BMDM were identified as by-products.

Computational study on the vinyl azide decomposition.

The decomposition mechanism of vinyl azide (CH2CHN3) has been studied by calculations of the electronic structure. In addition, a study based on the topology of the electron charge density distribution and its Laplacian function, within the Quantum Theory of Atoms in Molecules (QTAIM), has been carried out with the aim of comprehending the electron redistribution mechanisms that take place in the formation of vinyl nitrenes. The electronic structure calculations reveal that the decomposition of the s-cis conformer of vinyl azide leads to the formation of ketenimine through a single-step conversion, s-cis-CH2CHN3 → CH2CNH + N2, while the conversion of the s-trans conformer to acetonitrile occurs in two steps, s-trans-CH2CHN3 → cyc-CH2NCH + N2 → CH3CN + N2. The topological analysis of the L(r) function reveals that triplet vinyl nitrene has one lone pair on the valence shell charge concentration (VSCC) of nitrogen and thus could act as a monodentate Lewis base, while singlet vinyl nitrene has two lone pairs on the VSCC of nitrogen and thus could act as a bidentate Lewis base.

Structural, energetic, and UV-Vis spectral analysis of UVA filter 4-tert-butyl-4'-methoxydibenzoylmethane.

The growing awareness of the harmful effects of ultraviolet (UV) solar radiation has increased the production and consumption of sunscreen products, which contain organic and inorganic molecules named UV filters that absorb, reflect, or scatter UV radiation, thus minimizing negative human health effects. 4-tert-Butyl-4'-methoxydibenzoylmethane (BMDBM) is one of the few organic UVA filters and the most commonly used. BMDBM exists in sunscreens in the enol form which absorbs strongly in the UVA range. However, under sunlight irradiation tautomerization occurs to the keto form, resulting in the loss of UV protection. In this study we have performed quantum chemical calculations to study the excited-state molecular structure and excitation spectra of the enol and keto tautomers of BMDBM. This knowledge is of the utmost importance as the starting point for studies aiming at the understanding of its activity when applied on human skin and also its fate once released into the aquatic environment. The efficiency of excitation transitions was rationalized based on the concept of molecular orbital superposition. The loss of UV protection was attributed to the enol → keto phototautomerism and subsequent photodegradation. Although this process is not energetically favorable in the singlet bright state, photodegradation is possible because of intersystem crossing to the first two triplet states.

Contactless Resolution of Inflammatory Signals in Tailored Macrophage-Based Cell Therapeutics.

In recent years, nanotechnology-based microRNA (miR) therapeutic platforms have shown great promise for immunotherapy and tissue regeneration, despite the unmet challenge of achieving efficient and safe delivery of miRs. The transport of miRs offers precision and regulatory value for a myriad of biological processes and pathways, including the control of macrophage (Mφ) functions and, consequently, the inflammatory cascades Mφ are involved in. Thus, enforcement of Mφ can boost the regenerative process and provide new solutions for diverse chronic pathologies. In this study, we sought to develop a magnetically guided transporter to deliver an miR-155 antagonist to M1-primed Mφ. Furthermore, we determined its modulatory effect in reprogramming Mφ from inflammatory to pro-regenerative phenotypes, with the aim of tissue healing and regenerative medicine approaches. This strategy combines contactless and high-precision control of Mφ, anticipating new functional miR carriers for targeted strategies controlled by extracorporeal action. The magnetoplexes SPION@PEI-miR were efficiently delivered into Mφ without compromising cell viability and successfully induced miR-mediated gene silencing by enhancing the expression of anti-inflammatory markers (IL4 and IL10) and the production of M2φ-related markers (CD206 and IL4). Given its multimodal features, SPION@PEI-miR represents a simple, safe, and nonviral theranostic platform that enables imaging, tracking, and miR delivery with modulatory effects on immune cells.

Magnetic triggers in biomedical applications - prospects for contact free cell sensing and guidance.

In recent years, the inputs from magnetically assisted strategies have been contributing to the development of more sensitive screening methods and precise means of diagnosis to overcome existing and emerging treatment challenges. The features of magnetic materials enabling in vivo traceability, specific targeting and space- and time-controlled delivery of nanomedicines have highlighted the resourcefulness of the magnetic toolbox for biomedical applications and theranostic strategies. The breakthroughs in magnetically assisted technologies for contact-free control of cell and tissue fate opens new perspectives to improve healing and instruct regeneration reaching a wide range of diseases and disorders. In this review, the contribution of magnetic nanoparticles (MNPs) will be explored as sophisticated and versatile nanotriggers, evidencing their unique cues to probe and control cell function. As cells detect and engage external magnetic features, these approaches will be overviewed considering molecular engineering and cell programming perspectives as well as cell and tissue targeting modalities. The therapeutic relevance of MNPs will be also emphasized as key components of nanostructured systems to control the release of nanomedicines and in the context of new therapy technologies.

Remote triggering of TGF-ß/Smad2/3 signaling in human adipose stem cells laden on magnetic scaffolds synergistically promotes tenogenic commitment.

Injuries affecting load bearing tendon tissues are a significant clinical burden and efficient treatments are still unmet. Tackling tendon regeneration, tissue engineering strategies aim to develop functional substitutes that recreate native tendon milieu. Tendon mimetic scaffolds capable of remote magnetic responsiveness and functionalized magnetic nanoparticles (MNPs) targeting cellular mechanosensitive receptors are potential instructive tools to mediate mechanotransduction in guiding tenogenic responses. In this work, we combine magnetically responsive scaffolds and targeted Activin A type II receptor in human adipose stem cells (hASCs), under alternating magnetic field (AMF), to synergistically facilitate external control over signal transduction. The combination of remote triggering TGF-ß/Smad2/3 using MNPs tagged hASCs, through magnetically actuated scaffolds, stimulates overall expression of tendon related genes and the deposition of tendon related proteins, in comparison to non-stimulated conditions. Moreover, the phosphorylation of Smad2/3 proteins and their nuclear co-localization was also more evident. Overall, biophysical stimuli resulting from magnetic scaffolds and magnetically triggered cells under AMF stimulation modulate the mechanosensing response of hASCs towards tenogenesis, holding therapeutic promise. STATEMENT OF SIGNIFICANCE: The concept of magnetically-assisted tissue engineering may assist the development of innovative solutions to treat tendon disorders upon remote control of biological processes as cell migration or differentiation. Herein, we originally combine a fibrous aligned superparamagnetic scaffold, based on a biodegradable polymeric blend of starch and poly-ɛ-caprolactone incorporating magnetic nanoparticles (MNPs), and human adipose stem cells (hASCs) labelled with MNPs functionalized with anti-activin receptor type IIA (ActRIIA). Constructs were stimulated using alternating magnetic field (AMF), to activate the ActRIIA and subsequent induction of TGF-ß signaling, through Smad2/3 phosphorylation cascade, enhancing the expression of tendon-related markers. Altogether, these findings contribute with powerful bio-magnetic approaches to activate key tenogenic pathways, envisioning future translation of magnetic biomaterials into regenerative platforms for tendon repair.

Energetics of coumarin and chromone.

Condensed phase standard (p degrees = 0.1 MPa) molar enthalpies of formation for coumarin and chromone were derived from the standard molar enthalpies of combustion, in oxygen, at T = 298.15 K, measured by static bomb combustion calorimetry. The standard molar enthalpies of sublimation, at T = 298.15 K, were measured by Calvet microcalorimetry. Combining these values, the following enthalpies of formation in the gas phase, at T = 298.15 K, were then derived: coumarin, -(163.4 +/- 3.3) kJ x mol(-1), and chromone, -(126.1 +/- 2.5) kJ x mol(-1). The temperatures of fusion, T(fusion), and fusion enthalpies, at T = T(fusion), were also reported. Additionally, theoretical calculations were done using different methods: DFT/B3LYP, MCCM (MC-UT/3 and MC-QCISD/3), and also the more accurate G3MP2 method. Good agreement between experimental and theoretical data was achieved. Some correlations between structure and energy were also made, and the aromaticity of the compounds was evaluated by the nucleus independent chemical shifts (NICS).

Calorimetric and computational thermochemical study of 3,3-tetramethyleneglutaric acid, 3,3-tetramethyleneglutaric anhydride, and 3,3-tetramethyleneglutarimide.

The standard (p(o) = 0.1 MPa) molar energies of combustion in oxygen, at T = 298.15 K, of solid 3,3-tetramethyleneglutaric acid and the related 3,3-tetramethyleneglutaric anhydride and 3,3-tetramethyleneglutarimide were measured by static bomb combustion calorimetry. The values of the standard molar enthalpies of sublimation, at T = 298.15 K, were obtained by Calvet microcalorimetry, allowing the calculation of the standard molar enthalpies of formation of the compounds, in the gaseous state, at T = 298.15 K. The geometries of the experimentally studied compounds were fully optimized using density functional theory with the B3LYP functional and extended basis sets. More accurate energies were also obtained from single-point calculations at the most stable B3LYP/6-311G** geometries, using the cc-pVTZ basis set. From these calculations the standard molar enthalpies of formation of 3,3-tetramethyleneglutaric acid, 3,3-tetramethyleneglutaric anhydride, and 3,3-tetramethyleneglutarimide were estimated using isodesmic reactions involving glutaric acid, glutaric anhydride, and glutarimide, respectively. Experimental and computational results were used in the discussion of the interrelation of energetics and structure in these compounds and compared with other structurally related compounds.

Magnetic responsive cell-based strategies for diagnostics and therapeutics.

The potential of magnetically assisted strategies within the remit of cell-based therapies is increasing, creating new opportunities for biomedical platforms and in the field of tissue engineering and regenerative medicine. Among the magnetic elements approached for building magnetically responsive strategies, superparamagnetic iron oxide nanoparticles (SPIONs) represent tunable and precise tools whose properties can be modelled for detection, diagnosis, targeting and therapy purposes. The most investigated clinical role of SPIONs is as contrast imaging agents for tracking and monitoring cells and tissues. Nevertheless, magnetic detection also includes biomarker mapping, cell labelling and cell/drug targeting to monitor cell events and anticipate the disruption of homeostatic conditions and the progression of disease. Additionally, the isolation and screening techniques of cell subsets in heterogeneous populations or of proteins of interest have been explored in a magnetic sorting context. More recently, SPION-based technologies have been applied to stimulate cell differentiation and mechanotransduction processes and to transport genetic or drug cargo to study biological mechanisms and contribute to improved therapies. Magnetically based strategies significantly contribute to magnetic tissue engineering (magTE), in which magnetically responsive actuators built from magnetic labelled cells or magnetic functionalized systems can be remotely controlled and spatially manipulated upon the actuation of an external magnetic field for the delivery or target of TE solutions. SPION functionalities combined with magnetic responsiveness in multifactorial magnetically assisted platforms can revolutionize diagnosis and therapeutics, providing new diagnosis and theranostic tools, encouraging regenerative medicine approaches and having potential for more effective therapies. This review will address the contribution of SPION-based technologies as multifunctional tools in boosting magnetically assisted cell-based strategies to explore diagnostics and tracking solutions for the detection and analysis of pathologies, and to generate improved treatments and therapies, envisioning precise and customized answers for the management of numerous diseases.

Exploring inhalable polymeric dry powders for anti-tuberculosis drug delivery.

The growing interest on polymeric delivery systems for pulmonary administration of drugs anticipates a more direct and efficient treatment of diseases such as tuberculosis (TB) that uses the pulmonary route as the natural route of infection. Polymeric microparticles or nano-in-microparticles offer target delivery of drugs to the lungs and the potential to control and sustain drug release within TB infected macrophages improving the efficiency of the anti-TB treatment and reducing side effects. In a dry powder form these inhalable delivery systems have increased stability and prolonged storage time without requiring refrigeration, besides being cost-effective and patient convenient. Thus, this review aims to compile the recent innovations of inhalable polymeric dry powder systems for the delivery of anti-TB drugs exploring the methods of production, aerodynamic characterization and the efficacy of targeted drug delivery systems using in vitro and in vivo models of the disease. Advanced knowledge and promising outcomes of these systems are anticipated to simplify and revolutionize the pulmonary drug delivery and to contribute towards more effective anti-TB treatments.

Development of Inhalable Superparamagnetic Iron Oxide Nanoparticles (SPIONs) in Microparticulate System for Antituberculosis Drug Delivery.

Tuberculosis (TB) is an infectious disease which affects millions of people worldwide. Inhalable polymeric dry powders are promising alternatives as anti-TB drug carriers to the alveoli milieu and infected macrophages, with potential to significantly improve the therapeutics efficiency. Here, the development of a magnetically responsive microparticulate system for pulmonary delivery of an anti-TB drug candidate (P3) is reported. Microparticles (MPs) are developed based on a cast method using calcium carbonate sacrificial templates and incorporate superparamagnetic iron oxide nanoparticles to concentrate MPs in alveoli and enable drug on demand release upon actuation of an external alternate magnetic field (AMF). The MPs are shown to be suitable for P3 delivery to the lower airways and for alveolar macrophage phagocytosis. The developed MPs reveal unique and promising features to be used as an inhalable dry powder allowing the AMF control over dosage and frequency of drug delivery anticipating improved TB treatments.

Study of the transformation of two salicylates used in personal care products in chlorinated water.

Disinfection of swimming pool water is essential to inactivate pathogenic microorganisms. However chlorine based disinfectants, the most commonly used, are known to lead to the formation of disinfection by-products (DBPs), some of which have been associated with adverse health effects. Precursors of DBPs include the organic matter present in the water used to fill the swimming pool, human body fluids and personal care products (PCPs) used by swimmers and bathers. The increased use, in the last years, of PCPs lead to an increased concern about the fate of PCPs in swimming pool waters and potential health risks of formed DBPs. In this study, the chemical transformations of two salicylates, benzyl salicylate (BzS) and phenyl salicylate (PS), incorporated in several PCPs, in chlorinated water were investigated. High-performance liquid chromatography (HPLC) with UV-diode-array detection (HPLC-UV-DAD) was used to follow the reaction kinetics and HPLC with mass spectrometry (HPLC-MS) was used to tentatively identify the major transformation by-products. Under the experimental conditions used in this work both salicylates reacted with chlorine following pseudo-first order kinetics: rate constant k = (0.0038 ± 0.0002) min(-1) and half-life t1/2 = (182 ± 10) min for BzS and rate constant k = (0.0088 ± 0.0005) min(-1) and half-life t1/2 = (79 ± 4) min for PS (mean ± standard deviation). The reactions of the two salicylates in chlorinated water led to the formation of DBPs that were tentatively identified as mono- and dichloro- substituted compounds. Most probably they result from an electrophilic substitution of one or two hydrogen atoms in the phenolic ring of both salicylates by one or two chlorine atoms.

Photodegradation of avobenzone: stabilization effect of antioxidants.

Avobenzone is one of the most common UVA-filters in sunscreens, and is known to be photounstable. Some of the strategies used to stabilize this filter present some drawbacks like photosensitization reactions. Antioxidants are widely used as cosmetic ingredients that prevent photoageing and complement the photoprotection offered by the UV-filters preventing or reducing photogenerated reactive species. The purpose of this work was to study the effect of antioxidants in the photostabilization of avobenzone. The filter dissolved in dimethyl sulfoxide or incorporated in a sunscreen formulation was irradiated with simulated solar radiation (750 W/m(2)). The tested antioxidants were vitamin C, vitamin E, and ubiquinone. The area under the curve of the absorption spectrum for UVA range and the sun protection factor (SPF) were calculated. Vitamin E (1:2), vitamin C (1:0.5) and ubiquinone (1:0.5) were the more effective concentrations increasing the photostability of avobenzone. In sunscreen formulations, the most effective photostabilizer was ubiquinone which also promoted an increase in SPF. This knowledge is important to improve effectiveness of sunscreen formulation. Antioxidants can be valuable ingredients for sunscreens with a triple activity of filter stabilization, SPF boosting and photoageing prevention.

Amino, Ammonio and Aminioethenes: A Theoretical Study of their Structure and Energetics.

We have performed high level ab initio quantum mechanical calculations for aminoethene and the three isomeric 1,1- (Z)- or (E)-1,2-diaminoethenes as well as their singly and doubly charged cations derived by loss of electrons and/or upon protonation. Gas phase molecular structures were computed at the MP2/6-311+G(3df,2p) level. Standard molar enthalpies of formation in the gas phase, at T = 298.15 K were estimated using the G3 composite method and atomization, isodesmic and homodesmotic reactions. Other energetic parameters were also calculated at the G3 level: proton affinities, basicities and adiabatic ionization enthalpies. Theoretical and experimental data are compared. The reported experimental data refer only to aminoethene wherein the standard molar enthalpy of formation has a considerable uncertainty, although the molecular structure is well-established. There are no such data, neither structural nor thermochemical, for any of the three isomeric diaminoethenes. Isoelectronic comparisons are made. For example, the diprotonated diaminoethenes are isoelectronic to isobutene and (Z)- and (E)-butene, while the doubly ionized diaminoethenes are likewise related to trimethylenemethane and 1,3-butadiene.

The degradation products of UV filters in aqueous and chlorinated aqueous solutions.

Ultraviolet (UV) filters are vital constituents of sunscreens and other personal care products since they absorb, reflect and/or scatter UV radiation, therefore protecting us from the sun's deleterious UV radiation and its effects. However, they suffer degradation, mainly through exposure towards sunlight and from reactions with disinfectant products such as chlorine. On the basis of their increasing production and use, UV filters and their degradation products have already been detected in the aquatic environment, especially in bathing waters. This paper presents a comprehensive review on the work done so far as to identify and determine the by-products of UV filter photodegradation in aqueous solutions and those subsequent to disinfection-induced degradation in chlorinated aqueous solutions, namely swimming pools.

Study of energetics and structure of 1,2,3-benzotriazin-4(3H)-one and its 1H and enol tautomers.

This paper reports an experimental and computational study on the energetics of 1,2,3-benzotriazin-4(3H)-one. The standard (p° = 0.1 MPa) molar enthalpy of formation of solid 1,2,3-benzotriazin-4(3H)-one, at T = 298.15 K, was derived from its standard massic energy of combustion measured by static bomb combustion calorimetry in oxygen. The Calvet high-temperature vacuum sublimation technique was used to measure the respective standard molar enthalpy of sublimation at T = 298.15 K. From these two experimentally determined thermodynamic parameters, we have calculated the standard molar enthalpy of formation of 1,2,3-benzotriazin-4(3H)-one in the gas phase at T = 298.15 K, (200.9 ± 3.8) kJ·mol(-1). Interrelations between structure and energy for 1,2,3-benzotriazin-4(3H)-one, the tautomer 1,2,3-benzotriazin-4(1H)-one, and the enol tautomer 1,2,3-benzotriazin-4-ol were discussed based on density functional theory (DFT) calculations with the B3LYP hybrid functional and the 6-311++G(d,p) basis set. The gas-phase enthalpy of formation of 1,2,3-benzotriazin-4(3H)-one was estimated from quantum chemical calculations using the G3(MP2)//B3LYP composite method. Nucleus-independent chemical shifts (NICS) were also calculated with the purpose of analyzing the aromaticity of the benzenic and heterocyclic rings of the title molecule and others related tautomerically to it.

The experimental and calculational thermochemistry of 1,2,4,5-benzenetetracarboxylic dianhydride: is this 10 pi multiring species aromatic?

The standard (p degrees = 0.1 MPa) molar enthalpy of formation of 1,2,4,5-benzenetetracarboxylic dianhydride in the gaseous phase, -826.8 +/- 3.1 kJ mol-1, was derived from the standard molar enthalpy of combustion, in oxygen, at T = 298.15 K, measured by static bomb combustion calorimetry and the standard molar enthalpy of sublimation, at T = 298.15 K, measured by Calvet microcalorimetry. In addition, density functional theory calculations have been performed with the B3LYP, MPW1B95, and B3PW91 density functionals and the cc-pVTZ basis set for 1,2,4,5-benzenetetracarboxylic dianhydride and 1,2,4,5-benzenetetracarboxylic diimide. Nucleus-independent chemical shifts calculations show that the aromaticity is restricted to the benzenic ring in both compounds even though they are formally 10 pi polynuclear species.