Predicting Skin Permeability by means of Computational Approaches : Reliability and Caveats in Pharmaceutical Studies

© 2019 American Chemical Society.The skin is the main barrier between the internal body environment and the external one. The characteristics of this barrier and its properties are able to modify and affect drug delivery and chemical toxicity parameters. Therefore, it is not surprising that permeability of many different compounds has been measured through several in vitro and in vivo techniques. Moreover, many different in silico approaches have been used to identify the correlation between the structure of the permeants and their permeability, to reproduce the skin behavior, and to predict the ability of specific chemicals to permeate this barrier. A significant number of issues, like interlaboratory variability, experimental conditions, data set building rationales, and skin site of origin and hydration, still prevent us from obtaining a definitive predictive skin permeability model. This review wants to show the main advances and the principal approaches in computational methods used to predict this property, to enlighten the main issues that have arisen, and to address the challenges to develop in future research.Peer reviewedFinal Accepted Versio

Novel Techniques and Their Applications to Health Foods, Agricultural and Medical Biotechnology: Functional Genomics and Basic Epigenetic Controls in Plant and Animal Cells

Selected applications of novel techniques for analyzing Health Food formulations, as well as for advanced investigations in Agricultural and Medical Biotechnology aimed at defining the multiple connections between functional genomics and epigenomic, fundamental control mechanisms in both animal and plant cells are being reviewed with the aim of unraveling future developments and policy changes that are likely to open new niches for Biotechnology and prevent the shrinking or closing of existing markets. Amongst the selected novel techniques with applications in both Agricultural and Medical Biotechnology are: immobilized bacterial cells and enzymes, microencapsulation and liposome production, genetic manipulation of microorganisms, development of novel vaccines from plants, epigenomics of mammalian cells and organisms, and biocomputational tools for molecular modeling related to disease and Bioinformatics. Both fundamental and applied aspects of the emerging new techniques are being discussed in relation to their anticipated, marked impact on future markets and present policy changes that are needed for success in either Agricultural or Medical Biotechnology. The novel techniques are illustrated with figures presenting the most important features of representative and powerful tools which are currently being developed for both immediate and long term applications in Agriculture, Health Food formulation and production, pharmaceuticals and Medicine. The research aspects are naturally emphasized in our review as they are key to further developments in Biotechnology; however, the course adopted for the implementation of biotechnological applications, and the policies associated with biotechnological applications are clearly the determining factors for future Biotechnology successes, be they pharmaceutical, medical or agricultural

Recent advances in smart biotechnology: Hydrogels and nanocarriers for tailored bioactive molecules depot

Over the past ten years, the global biopharmaceutical market has remarkably grown, with ten over the top twenty worldwide high performance medical treatment sales being biologics. Thus, biotech R&D (research and development) sector is becoming a key leading branch, with expanding revenues. Biotechnology offers considerable advantages compared to traditional therapeutic approaches, such as reducing side effects, specific treatments, higher patient compliance and therefore more effective treatments leading to lower healthcare costs. Within this sector, smart nanotechnology and colloidal self-assembling systems represent pivotal tools able to modulate the delivery of therapeutics. A comprehensive understanding of the processes involved in the self assembly of the colloidal structures discussed therein is essential for the development of relevant biomedical applications. In this review we report the most promising and best performing platforms for specific classes of bioactive molecules and related target, spanning from siRNAs, gene/plasmids, proteins/growth factors, small synthetic therapeutics and bioimaging probes.Istituto Italiano di Tecnologia (IIT)COST Action [CA 15107]People Program (Marie Curie Actions) of the European Union's Seventh Framework Program under REA [606713 BIBAFOODS]Portuguese Foundation for Science and Technology (FCT) [PTDC/AGR-TEC/4814/2014, IF/01005/2014]Fundacao para a Ciencia e Tecnologia [SFRH/BPD/99982/2014]Danish National Research Foundation [DNRF 122]Villum Foundation [9301]Italian Ministry of Instruction, University and Research (MIUR), PRIN [20109PLMH2]"Fondazione Beneficentia Stiftung" VaduzFondo di Ateneo FRAFRAinfo:eu-repo/semantics/publishedVersio

The role of ultrasound-driven microbubble dynamics in drug delivery : from microbubble fundamentals to clinical translation

In the last couple of decades, ultrasound-driven microbubbles have proven excellent candidates for local drug delivery applications. Besides being useful drug carriers, microbubbles have demonstrated the ability to enhance cell and tissue permeability and, as a consequence, drug uptake herein. Notwithstanding the large amount of evidence for their therapeutic efficacy, open issues remain. Because of the vast number of ultrasound- and microbubble-related parameters that can be altered and the variability in different models, the translation from basic research to (pre)clinical studies has been hindered. This review aims at connecting the knowledge gained from fundamental microbubble studies to the therapeutic efficacy seen in in vitro and in vivo studies, with an emphasis on a better understanding of the response of a microbubble upon exposure to ultrasound and its interaction with cells and tissues. More specifically, we address the acoustic settings and microbubble-related parameters (i.e., bubble size and physicochemistry of the bubble shell) that play a key role in microbubble cell interactions and in the associated therapeutic outcome. Additionally, new techniques that may provide additional control over the treatment, such as monodisperse microbubble formulations, tunable ultrasound scanners, and cavitation detection techniques, are discussed. An in-depth understanding of the aspects presented in this work could eventually lead the way to more efficient and tailored microbubble-assisted ultrasound therapy in the future

Deformable Nanovesicles Synthesized through an Adaptable Microfluidic Platform for Enhanced Localized Transdermal Drug Delivery.

Phospholipid-based deformable nanovesicles (DNVs) that have flexibility in shape offer an adaptable and facile method to encapsulate diverse classes of therapeutics and facilitate localized transdermal delivery while minimizing systemic exposure. Here we report the use of a microfluidic reactor for the synthesis of DNVs and show that alteration of input parameters such as flow speeds as well as molar and flow rate ratios increases entrapment efficiency of drugs and allows fine-tuning of DNV size, elasticity, and surface charge. To determine the ability of DNV-encapsulated drug to be delivered transdermally to a local site, we synthesized, characterized, and tested DNVs carrying the fluorescently labeled hydrophilic bisphosphonate drug AF-647 zoledronate (AF647-Zol). AF647-Zol DNVs were lyophilized, resuspended, and applied topically as a paste to the calvarial skin of mice. High-resolution fluorescent imaging and confocal microscopy revealed significant increase of encapsulated payload delivery to the target tissue-cranial bone-by DNVs as compared to nondeformable nanovesicles (NVs) or aqueous drug solutions. Interestingly, NV delivery was not superior to aqueous drug solution. Our studies show that microfluidic reactor-synthesized DNVs can be produced in good yield, with high encapsulation efficiency, reproducibility, and stability after storage, and represent a useful vehicle for localized transdermal drug delivery

Recent Advances in Encapsulation, Protection, and Oral Delivery of Bioactive Proteins and Peptides using Colloidal Systems

There are many areas in medicine and industry where it would be advantageous to orally deliver bioactive proteins and peptides (BPPs), including ACE inhibitors, antimicrobials, antioxidants, hormones, enzymes, and vaccines. A major challenge in this area is that many BPPs degrade during storage of the product or during passage through the human gut, thereby losing their activity. Moreover, many BPPs have undesirable taste profiles (such as bitterness or astringency), which makes them unpleasant to consume. These challenges can often be overcome by encapsulating them within colloidal particles that protect them from any adverse conditions in their environment, but then release them at the desired site-of-action, which may be inside the gut or body. This article begins with a discussion of BPP characteristics and the hurdles involved in their delivery. It then highlights the characteristics of colloidal particles that can be manipulated to create effective BPP-delivery systems, including particle composition, size, and interfacial properties. The factors impacting the functional performance of colloidal delivery systems are then highlighted, including their loading capacity, encapsulation efficiency, protective properties, retention/release properties, and stability. Different kinds of colloidal delivery systems suitable for encapsulation of BPPs are then reviewed, such as microemulsions, emulsions, solid lipid particles, liposomes, and microgels. Finally, some examples of the use of colloidal delivery systems for delivery of specific BPPs are given, including hormones, enzymes, vaccines, antimicrobials, and ACE inhibitors. An emphasis is on the development of food-grade colloidal delivery systems, which could be used in functional or medical food applications. The knowledge presented should facilitate the design of more effective vehicles for the oral delivery of bioactive proteins and peptides

Micellar drug nanocarriers and biomembranes: how do they interact?

Pluronic based formulations are among the most successful nanomedicines and block-copolymer micelles including drugs that are undergoing phase I/II studies as anticancer agents. Using coarse-grained models, molecular dynamics simulations of large-scale systems, modeling Pluronic micelles interacting with DPPC lipid bilayers, on the μs timescale have been performed. Simulations show, in agreement with experiments, the release of Pluronic chains from the micelle to the bilayer. This release changes the size of the micelle. Moreover, the presence of drug molecules inside the core of the micelle has a strong influence on this process. The picture emerging from the simulations is that the micelle stability is a result of an interplay of drug–micelle core and block-copolymer–bilayer interactions. The equilibrium size of the drug vector shows a strong dependency on the hydrophobicity of the drug molecules embedded in the core of the micelle. In particular, the radius of the micelle shows an abrupt increase in a very narrow range of drug molecule hydrophobicity

Polymeric versus lipid nanoparticles: comparative study of nanoparticulate systems as indomethacin carriers

Encapsulation of nonsteroidal or non-steroidal anti-inflammatory drugs (NSAID) in nanocarrier systems aims to enhance bioavailability and to decrease toxicity of these drugs and thus improve the efficacy of treatments. With this aim two types of nanoparticles were prepared and compared: lipid nanoparticles, made of cetyl palmitate and Miglyol 812 which were uncoated or coated with chitosan; or polymeric nanoparticles, made of poly (DL-lactic-co-glycolic acid) (PLGA) for which different emulsion stabilizers were also tested (poly (vinyl alcohol) (PVA), and Pluronic F68). Nanoparticles were characterized for drug content and for particle size, charge and morphology. The lipid matrix was analyzed regarding its crystallinity by differential scanning calorimetry (DSC). The size of the nanoparticles was measured by dynamic light scattering (DLS) which indicated a unimodal particle size distribution in all systems. Nanoparticles’ stability was confirmed by their highly negative surface charge in the case of polymeric and uncoated lipid nanoparticles, as analyzed by zeta potential measurements using electrophoretic light scattering (ELS). Lipid chitosan coated nanoparticles have also shown to be stable presenting highly positive surface charge. Results have further demonstrated that indomethacin is highly encapsulated regardless the type of particles. Morphological analysis by scanning electron microscopy has shown that the nanoparticles were smooth and spherical. The results gathered within the current study point to the conclusion that the proposed formulations provide nanoparticles of satisfactory quality to encapsulate indomethacin, which might be used to improve bioavailability of other NSAID in the treatment of inflammation.This work was supported by FEDER through POFC – COMPETE and by national funds from FCT through the projects PEst-C/FIS/UI0607/2013 (CFUM). Marlene Lucio holds a position of Researcher FCT with the reference IF/00498/2012. We acknowledge NanoDelivery-I&D em Bionanotecnologia, Lda for access to their equipment.info:eu-repo/semantics/publishedVersio