Subcellular Carrier-Based Optical Ion-Selective Nanosensors

In this review, two carrier systems based on nanotechnology for real-time sensing of biologically relevant analytes (ions or other biological molecules) inside cells in a non-invasive way are discussed. One system is based on inorganic nanoparticles with an organic coating, whereas the second system is based on organic microcapsules. The sensor molecules presented within this work use an optical read-out. Due to the different physicochemical properties, both sensors show distinctive geometries that directly affect their internalization patterns. The nanoparticles carry the sensor molecule attached to their surfaces whereas the microcapsules encapsulate the sensor within their cavities. Their different size (nano and micro) enable each sensors to locate in different cellular regions. For example, the nanoparticles are mostly found in endolysosomal compartments but the microcapsules are rather found in phagolysosomal vesicles. Thus, allowing creating a tool of sensors that sense differently. Both sensor systems enable to measure ratiometrically however, only the microcapsules have the unique ability of multiplexing. At the end, an outlook on how more sophisticated sensors can be created by confining the nano-scaled sensors within the microcapsules will be given

Magnetically triggered release of molecular cargo from iron oxide nanoparticle loaded microcapsules

Iron oxide nanocube-modified microcapsules as a platform for magnetically triggered molecular release

Assessing the Potential of Molecular Imaging for Myelin Quantification in Organotypic Cultures

Ex vivo models for the noninvasive study of myelin-related diseases represent an essential tool to understand the mechanisms of diseases and develop therapies against them. Herein, we assessed the potential of multimodal imaging traceable myelin-targeting liposomes to quantify myelin in organotypic cultures. Methods: MRI testing was used to image mouse cerebellar tissue sections and organotypic cultures. Demyelination was induced by lysolecithin treatment. Myelin-targeting liposomes were synthetized and characterized, and their capacity to quantify myelin was tested by fluorescence imaging. Results: Imaging of freshly excised tissue sections ranging from 300 µm to 1 mm in thickness was achieved with good contrast between white (WM) and gray matter (GM) using T2w MRI. The typical loss of stiffness, WM structures, and thickness of organotypic cultures required the use of diffusion-weighted methods. Designed myelin-targeting liposomes allowed for semiquantitative detection by fluorescence, but the specificity for myelin was not consistent between assays due to the unspecific binding of liposomes. Conclusions: With respect to the sensitivity, imaging of brain tissue sections and organotypic cultures by MRI is feasible, and myelin-targeting nanosystems are a promising solution to quantify myelin ex vivo. With respect to specificity, fine tuning of the probe is required. Lipid-based systems may not be suitable for this goal, due to unspecific binding to tissues

Delayed alveolar clearance of nanoparticles through control of coating composition and interaction with lung surfactant protein A

The coating composition of nanomedicines is one of the main features in determining the medicines' fate, clearance, and immunoresponse in the body. To highlight the coatings' impact in pulmonary administration, two micellar superparamagnetic iron oxide nanoparticles (SPION) were compared. These nanoparticles are similar in size and charge but have different coatings: either phosphatidylcholine (PC-SPION) or bovine serum albumin (BSA-SPION). The aim of the study was to increase the understanding of the nano-bio interaction with the cellular and non-cellular components of the lung and underline valuable coatings either for local lung-targeted drug delivery in theranostic application or patient-friendly route systemic administration. PC-SPION and BSA-SPION were deposited in the alveoli by in vivo instillation and, despite the complexity of imaging the lung, SPION were macroscopically visualized by MRI. Impressively, PC-SPION were retained within the lungs for at least a week, while BSA-SPION were cleared more rapidly. The different lung residence times were confirmed by histological analysis and supported by a flow cytometry analysis of the SPION interactions with different myeloid cell populations. To further comprehend the way in which these nanoformulations interact with lung components at the molecular level, we used fluorescence spectroscopy, turbidity measurements, and dynamic light scattering to evaluate the interactions of the two SPION with surfactant protein A (SP-A), a key protein in setting up the nanoparticle behavior in the alveolar fluid. We found that SP-A induced aggregation of PC-SPION, but not BSA-SPION, which likely caused PC-SPION retention in the lung without inducing inflammation. In conclusion, the two SPION show different outcomes from interaction with SP-A leading to distinctive fate in the lung. PC-SPION hold great promise as imaging and theranostic agents when prolonged pulmonary drug delivery is required

MiR-219a-5p Enriched Extracellular Vesicles Induce OPC Differentiation and EAE Improvement More Efficiently Than Liposomes and Polymeric Nanoparticles

Remyelination is a key aspect in multiple sclerosis pathology and a special effort is being made to promote it. However, there is still no available treatment to regenerate myelin and several strategies are being scrutinized. Myelination is naturally performed by oligodendrocytes and microRNAs have been postulated as a promising tool to induce oligodendrocyte precursor cell differentiation and therefore remyelination. Herein, DSPC liposomes and PLGA nanoparticles were studied for miR-219a-5p encapsulation, release and remyelination promotion. In parallel, they were compared with biologically engineered extracellular vesicles overexpressing miR-219a-5p. Interestingly, extracellular vesicles showed the highest oligodendrocyte precursor cell differentiation levels and were more effective than liposomes and polymeric nanoparticles crossing the blood–brain barrier. Finally, extracellular vesicles were able to improve EAE animal model clinical evolution. Our results indicate that the use of extracellular vesicles as miR-219a-5p delivery system can be a feasible and promising strategy to induce remyelination in multiple sclerosis patients.This work was supported by Carlos III Institute, (PI17/00189 and DTS15/00069), by Fondo Europeo de Desarrollo Regional—FEDER, by the Gipuzkoa Regional Council (DFG 15/006), by grant from the Basque Government (RIS3/DTS/2018222025), by the Department of Industry of the Basque Country (ELKARTEK 16/014), and the Spanish State Research Agency (SAF2017-87670-R) and Maria de Maeztu Units of Excellence Program Grant MDM-2017-0720). I.O.-Q., A.A. and L.I. were supported by the Department of Education of the Basque Government. IOQ and LAN were supported by EMBO short Term Fellowship Programme. LAN was supported by a Canadian graduate scholarship from the Canadian Institutes of Health Research (CGS-D CIHR).PRC was supported by Ikerbasque, the Basque Foundation for Science

Ultrasmall manganese ferrites for in vivo catalase mimicking activity and multimodal bioimaging

Manganese ferrite nanoparticles display interesting features in bioimaging and catalytic therapies. They have been recently used in theranostics as contrast agents in magnetic resonance imaging (MRI), and as catalase-mimicking nanozymes for hypoxia alleviation. These promising applications encourage the development of novel synthetic procedures to enhance the bioimaging and catalytic properties of these nanomaterials simultaneously. Herein, a cost-efficient synthetic microwave method is developed to manufacture ultrasmall manganese ferrite nanoparticles as advanced multimodal contrast agents in MRI and positron emission tomography (PET), and improved nanozymes. Such a synthetic method allows doping ferrites with Mn in a wide stoichiometric range (MnxFe3-xO4, 0.1 ≤ x ≤ 2.4), affording a library of nanoparticles with different magnetic relaxivities and catalytic properties. These tuned magnetic properties give rise to either positive or dual-mode MRI contrast agents. On the other hand, higher levels of Mn doping enhance the catalytic efficiency of the resulting nanozymes. Finally, through their intracellular catalase-mimicking activity, these ultrasmall manganese ferrite nanoparticles induce an unprecedented tumor growth inhibition in a breast cancer murine model. All of these results show the robust characteristics of these nanoparticles for nanobiotechnological applications.The authors thank M. Jeannin from Lasie Laboratory (La Rochelle University) for the Raman studies. S.C.R. is supported by the grant PID2019-106139RA-100 funded by MCIN. J.R.-C. is supported by grants from the Ministerio de Economía, Industria y Competitividad (MEIC) (SAF2017-84494-C2-R). J.R.C. received funding from the BBVA Foundation (PR [18]_BIO_IMG_0008) and La Caixa (HR18-00052). Y.F.-A. received funding from the Santander-Universidad Zaragoza Fellowship program. L.G. acknowledges financial support from the Ramón y Cajal program (RYC-2014-15512). CIC biomaGUNE is supported by the Maria de Maeztu Units of Excellence Program from the Spanish State Research Agency (MDM-2017-0720). The authors acknowledge the use of Servicio General de Apoyo a la Investigación-SAI, Universidad de Zaragoza. H.G. is supported by the Ligue contre le Cancer (CD16, CD17) and Région Nouvelle Aquitaine (Projet “Nanovect”). J.A.E. is supported by RTI2018-099357-B-I00, HFSP (RGP0016/2018), CIBERFES16/10/00282 and RED2018-102576-T. The CNIC is supported by the Pro-CNIC Foundation and by the Severo Ochoa of Excellence Program.Peer reviewe

Mitochondrial Na+ controls oxidative phosphorylation and hypoxic redox signalling

All metazoans depend on O2 delivery and consumption by the mitochondrial oxidative phosphorylation (OXPHOS) system to produce energy. A decrease in O2 availability (hypoxia) leads to profound metabolic rewiring. In addition, OXPHOS uses O2 to produce reactive oxygen species (ROS) that can drive cell adaptations through redox signalling, but also trigger cell damage1–4, and both phenomena occur in hypoxia4–8. However, the precise mechanism by which acute hypoxia triggers mitochondrial ROS production is still unknown. Ca2+ is one of the best known examples of an ion acting as a second messenger9, yet the role ascribed to Na+ is to serve as a mere mediator of membrane potential and collaborating in ion transport10. Here we show that Na+ acts as a second messenger regulating OXPHOS function and ROS production by modulating fluidity of the inner mitochondrial membrane (IMM). We found that a conformational shift in mitochondrial complex I during acute hypoxia11 drives the acidification of the matrix and solubilization of calcium phosphate precipitates. The concomitant increase in matrix free-Ca2+ activates the mitochondrial Na+/Ca2+ exchanger (NCLX), which imports Na+ into the matrix. Na+ interacts with phospholipids reducing IMM fluidity and mobility of free ubiquinone between complex II and complex III, but not inside supercomplexes. As a consequence, superoxide is produced at complex III, generating a redox signal. Inhibition of mitochondrial Na+ import through NCLX is sufficient to block this pathway, preventing adaptation to hypoxia. These results reveal that Na+ import into the mitochondrial matrix controls OXPHOS function and redox signalling through an unexpected interaction with phospholipids, with profound consequences in cellular metabolism

Silicon particles as trojan horses for potential cancer therapy

[EN] Background: Porous silicon particles (PSiPs) have been used extensively as drug delivery systems, loaded with chemical species for disease treatment. It is well known from silicon producers that silicon is characterized by a low reduction potential, which in the case of PSiPs promotes explosive oxidation reactions with energy yields exceeding that of trinitrotoluene (TNT). The functionalization of the silica layer with sugars prevents its solubilization, while further functionalization with an appropriate antibody enables increased bioaccumulation inside selected cells. Results: We present here an immunotherapy approach for potential cancer treatment. Our platform comprises the use of engineered silicon particles conjugated with a selective antibody. The conceptual advantage of our system is that after reaction, the particles are degraded into soluble and excretable biocomponents. Conclusions: In our study, we demonstrate in particular, specific targeting and destruction of cancer cells in vitro. The fact that the LD50 value of PSiPs-HER-2 for tumor cells was 15-fold lower than the LD50 value for control cells demonstrates very high in vitro specificity. This is the first important step on a long road towards the design and development of novel chemotherapeutic agents against cancer in general, and breast cancer in particular.The authors acknowledge financial support from the following projects FIS2009-07812, MAT2012-35040, PROMETEO/2010/043, CTQ2011-23167, CrossSERS, FP7 MC-IEF 329131, and HSFP (project RGP0052/2012) and Medcom Tech SA. Xiang Yu acknowledges support by the Chinese government (CSC, Nr. 2010691036).Fenollosa Esteve, R.; Garcia-Rico, E.; Alvarez, S.; Alvarez, R.; Yu, X.; Rodriguez, I.; Carregal-Romero, S.... (2014). Silicon particles as trojan horses for potential cancer therapy. 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MicroRNA Nanotherapeutics for Lung Targeting. Insights into Pulmonary Hypertension

In this review, the potential future role of microRNA-based therapies and their specific application in lung diseases is reported with special attention to pulmonary hypertension. Current limitations of these therapies will be pointed out in order to address the challenges that they need to face to reach clinical applications. In this context, the encapsulation of microRNA-based therapies in nanovectors has shown improvements as compared to chemically modified microRNAs toward enhanced stability, efficacy, reduced side effects, and local administration. All these concepts will contextualize in this review the recent achievements and expectations reported for the treatment of pulmonary hypertension

Light-Triggered Ruthenium-Catalyzed Allylcarbamate Cleavage in Biological Environments

The sandwich complex [Cp*Ru(eta(6)-pyrene)]-PF6 (Cp* = eta*-C-5(CH3)(5)) serves as a photoactivatable catalyst for the conversion of N-allylcarbamates into their amines in the presence of thiophenol under biorelevant conditions (water, air, plus aliphatic thiols) and even in mammalian cells. This new phototriggered substrate/catalyst pair points towards applications in chemical biology and medicinal chemistry where signal amplification is combined with spacial and temporal control