Nanomedicine Approaches to Negotiate Local Biobarriers for Topical Drug Delivery

AbstractTopical treatments have been widely adopted to address a broad range of conditions across multiple sites thanks to their convenience, versatility, and effectiveness. While bypassing systemic biobarriers and avoiding systemic side effects by delivering directly to the target tissue, topical treatments still face significant local biobarriers that limit their efficacy. The toolset available for nanodelivery systems and their inherent multifunctionality can contribute to simultaneously address otherwise intractable challenges related to barrier function evasion, drug solubility, bioavailability, pharmacokinetics, smart and sustained release, quantitative co‐delivery, and local targeting which are key to successful topical treatments. This review summarizes the outstanding challenges associated with the topical treatments of key diseases of the skin, mucosae, eyes, and ears, and highlights how nanodelivery systems are being developed to address them effectively

Porcine Organotypic Epicardial Slice Protocol: A Tool for the Study of Epicardium in Cardiovascular Research

The epicardium has recently gained interest in the cardiovascular field due to its capacity to support heart regeneration after ischemic injury. Models to study the epicardium of large animals in vitro are limited and mainly based on epicardial cell isolation/differentiation from stem cells, followed by 2D cells culture. In this method paper, we describe the procedure to obtain and culture 3D organotypic heart slices presenting an intact epicardium, as a novel model to study the epicardial physiology and activation. Epicardial slices are obtained from porcine hearts using a high-precision vibratome and retain a healthy epicardial layer embedded in its native extracellular environment and connected with other cardiac cells (cardiomyocytes, fibroblasts, vascular cells etc.). Epicardial slices can be cultured for 72 h, providing an ideal model for studying the epicardium physiology or perform pharmacological interventions/gene therapy approaches. We also report on methods to assesses the viability and composition of the epicardial slices, and evaluate their architecture in 3D through tissue decoloration. Finally, we present a potential application for a nanomaterial-based gene transfer method for tracking of epicardial cells within the slice. Crucially, given the similarity in morphology and physiology of porcine heart with its human counterpart, our system provides a platform for translational research while providing a clinically relevant and ethical alternative to the use of small animals in this type of research

Tailoring the degradation kinetics of mesoporous silicon structures through PEGylation

Injectable and implantable porosified silicon (pSi) carriers and devices for prolonged and controlled delivery of biotherapeutics offer great promise for treatment of various chronic ailments and acute conditions. Polyethylene glycols (PEGs) are important surface modifiers currently used in clinic mostly to avoid uptake of particlulates by reticulo-endothelial system (RES). In this work we show for the first time that covalent attachment of PEGs to the pSi surface can be used as a means to finely tune degradation kinetics of silicon structures. Seven PEGs with varying molecular weights (245, 333, 509, 686, 1214, 3400 and 5000Da) were employed and the degradation of PEGylated pSi hemispherical microparticles in simulated physiological conditions was monitored by means of ICP-AES, SEM and fluorimetry. Biocompatibility of the systems with human macrophages in vitro was also evaluated. The results clearly indicate that controlled PEGylation of silicon microparticles can offer a sensitive tool to finely tune their degradation kinetics and that the systems do not induce release of proinflammatory cytokines IL-6 and IL-8 in THP1 human macrophages

A designer peptide as a template for growing Au nanoclusters

A peptide was designed to generate a sub-nanometric template that guides the growth of fluorescent gold nanoclusters. The peptide was endorsed with nucleating moieties and a three-dimensional structure that arrests the growth of ultrasmall nanoparticles. The nanoclusters are not cytotoxic and can be found in the cytosol of cells

Correlated Heterospectral Lipidomics for Biomolecular Profiling of Remyelination in Multiple Sclerosis

Analyzing lipid composition and distribution within the brain is important to study white matter pathologies that present focal demyelination lesions, such as multiple sclerosis. Some lesions can endogenously re-form myelin sheaths. Therapies aim to enhance this repair process in order to reduce neurodegeneration and disability progression in patients. In this context, a lipidomic analysis providing both precise molecular classification and well-defined localization is crucial to detect changes in myelin lipid content. Here we develop a correlated heterospectral lipidomic (HSL) approach based on coregistered Raman spectroscopy, desorption electrospray ionization mass spectrometry (DESI-MS), and immunofluorescence imaging. We employ HSL to study the structural and compositional lipid profile of demyelination and remyelination in an induced focal demyelination mouse model and in multiple sclerosis lesions from patients ex vivo. Pixelwise coregistration of Raman spectroscopy and DESI-MS imaging generated a heterospectral map used to interrelate biomolecular structure and composition of myelin. Multivariate regression analysis enabled Raman-based assessment of highly specific lipid subtypes in complex tissue for the first time. This method revealed the temporal dynamics of remyelination and provided the first indication that newly formed myelin has a different lipid composition compared to normal myelin. HSL enables detailed molecular myelin characterization that can substantially improve upon the current understanding of remyelination in multiple sclerosis and provides a strategy to assess remyelination treatments in animal models

The Relationship Between Mono-Abundance and Mono-Age Stellar Populations in the Milky Way Disk

Studying the Milky Way disk structure using stars in narrow bins of [Fe/H] and [α/Fe] has recently been proposed as a powerful method to understand the Galactic thick and thin disk formation. It has been assumed so far that these mono-abundance populations (MAPs) are also coeval, or mono-age, populations. Here we study this relationship for a Milky Way chemodynamical model and show that equivalence between MAPs and mono-age populations exists only for the high-[α/Fe] tail, where the chemical evolution curves of different Galactic radii are far apart. At lower [α/Fe]-values an MAP is composed of stars with a range in ages, even for small observational uncertainties and a small MAP bin size. Due to the disk inside-out formation, for these MAPs younger stars are typically located at larger radii, which results in negative radial age gradients that can be as large as 2 Gyr kpc−1. Positive radial age gradients can result for MAPs at the lowest [α/Fe] and highest [Fe/H] end. Such variations with age prevent the simple interpretation of observations for which accurate ages are not available. Studying the variation with radius of the stellar surface density and scale height in our model, we find good agreement to recent analyses of the APOGEE red-clump (RC) sample when 1–4 Gyr old stars dominate (as expected for the RC). Our results suggest that the APOGEE data are consistent with a Milky Way model for which mono-age populations flare for all ages. We propose observational tests for the validity of our predictions and argue that using accurate age measurements, such as from asteroseismology, is crucial for putting constraints on Galactic formation and evolution

CHEMICAL CARTOGRAPHY with APOGEE: METALLICITY DISTRIBUTION FUNCTIONS and the CHEMICAL STRUCTURE of the MILKY WAY DISK

Using a sample of 69,919 red giants from the SDSS-III/APOGEE Data Release 12, we measure the distribution of stars in the [/Fe] versus [Fe/H] plane and the metallicity distribution functions (MDFs) across an unprecedented volume of the Milky Way disk, with radius 3 < R < 15 kpc and height kpc. Stars in the inner disk (R < 5 kpc) lie along a single track in [/Fe] versus [Fe/H], starting with -enhanced, metal-poor stars and ending at [/Fe] ∼ 0 and [Fe/H] ∼ +0.4. At larger radii we find two distinct sequences in [/Fe] versus [Fe/H] space, with a roughly solar- sequence that spans a decade in metallicity and a high- sequence that merges with the low- sequence at super-solar [Fe/H]. The location of the high- sequence is nearly constant across the disk