Focus on Extracellular Vesicles: Introducing the Next Small Big Thing

Intercellular communication was long thought to be regulated exclusively through direct contact between cells or via release of soluble molecules that transmit the signal by binding to a suitable receptor on the target cell, and/or via uptake into that cell. With the discovery of small secreted vesicular structures that contain complex cargo, both in their lumen and the lipid membrane that surrounds them, a new frontier of signal transduction was discovered. These “extracellular vesicles” (EV) were initially thought to be garbage bags through which the cell ejected its waste. Whilst this is a major function of one type of EV, i.e., apoptotic bodies, many EVs have intricate functions in intercellular communication and compound exchange; although their physiological roles are still ill-defined. Additionally, it is now becoming increasingly clear that EVs mediate disease progression and therefore studying EVs has ignited significant interests among researchers from various fields of life sciences. Consequently, the research effort into the pathogenic roles of EVs is significantly higher even though their protective roles are not well established. The “Focus on extracellular vesicles” series of reviews highlights the current state of the art regarding various topics in EV research, whilst this review serves as an introductory overview of EVs, their biogenesis and molecular composition.     

Focus on Extracellular Vesicles: Physiological Role and Signalling Properties of Extracellular Membrane Vesicles

Extracellular vesicles (EVs) are a heterogeneous population of secreted membrane vesicles, with distinct biogenesis routes, biophysical properties and different functions both in physiological conditions and in disease. The release of EVs is a widespread biological process, which is conserved across species. In recent years, numerous studies have demonstrated that several bioactive molecules are trafficked with(in) EVs, such as microRNAs, mRNAs, proteins and lipids. The understanding of their final impact on the biology of specific target cells remains matter of intense debate in the field. Also, EVs have attracted great interest as potential novel cell-free therapeutics. Here we describe the proposed physiological and pathological functions of EVs, with a particular focus on their molecular content. Also, we discuss the advances in the knowledge of the mechanisms regulating the secretion of EV-associated molecules and the specific pathways activated upon interaction with the target cell, highlighting the role of EVs in the context of the immune system and as mediators of the intercellular signalling in the brain.     

Binding and Fusion of Extracellular Vesicles to the Plasma Membrane of Their Cell Targets

Exosomes and ectosomes, extracellular vesicles of two types generated by all cells at multivesicular bodies and the plasma membrane, respectively, play critical roles in physiology and pathology. A key mechanism of their function, analogous for both types of vesicles, is the fusion of their membrane to the plasma membrane of specific target cells, followed by discharge to the cytoplasm of their luminal cargo containing proteins, RNAs, and DNA. Here we summarize the present knowledge about the interactions, binding and fusions of vesicles with the cell plasma membrane. The sequence initiates with dynamic interactions, during which vesicles roll over the plasma membrane, followed by the binding of specific membrane proteins to their cell receptors. Membrane binding is then converted rapidly into fusion by mechanisms analogous to those of retroviruses. Specifically, proteins of the extracellular vesicle membranes are structurally rearranged, and their hydrophobic sequences insert into the target cell plasma membrane which undergoes lipid reorganization, protein restructuring and membrane dimpling. Single fusions are not the only process of vesicle/cell interactions. Upon intracellular reassembly of their luminal cargoes, vesicles can be regenerated, released and fused horizontally to other target cells. Fusions of extracellular vesicles are relevant also for specific therapy processes, now intensely investigated.     

Techniques for the Assessment of Mucoadhesion in Drug Delivery Systems: An Overview

Abstract

In recent years mucoadhesive drug delivery systems have been developed for oral, buccal, nasal, ocular, rectal and vaginal routes for either systemic or local effects. Mucoadhesive drug delivery systems are presently being explored because of their potential advantages including increased residence time of the drug at the site of application, relatively rapid uptake of the drug into the systemic circulation, and enhanced bioavailability of the therapeutic agents. This review focuses on trends and techniques for mucoadhesion assessment which includes various experimental methods that have been used for the characterization of mucoadhesive polymers and/or delivery systems. These techniques are categorized into two methods, namely methods for mechanism assessment and methods for formulation evaluation. The techniques used to evaluate mecha nisms of mucoadhesion include atomic force microscopy, texture analysis, rheological, wetting and zeta potential measurements for the assessment of interactions between the mucoadhesive polymer/system and mucosal surface. The methods for the evaluation of mucoadhesion based formulations are also further classified as ex vivo, in vitro as well as pharmacokinetic methods. Hence, the techniques highlight the possibility of evaluating mucoadhesion phenomenon in spite of its complexity.     

Development of Drug Delivery Systems Based on Layered Hydroxides for Nanomedicine

Layered hydroxides (LHs) have recently fascinated researchers due to their wide application in various fields. These inorganic nanoparticles, with excellent features as nanocarriers in drug delivery systems, have the potential to play an important role in healthcare. Owing to their outstanding ion-exchange capacity, many organic pharmaceutical drugs have been intercalated into the interlayer galleries of LHs and, consequently, novel nanodrugs or smart drugs may revolutionize in the treatment of diseases. Layered hydroxides, as green nanoreservoirs with sustained drug release and cell targeting properties hold great promise of improving health and prolonging life.     

温敏凝胶原位植入给药系统的研究进展

采用温敏凝胶的原位给药系统是理想的长效给药系统。该文从凝胶材料和给药系统的制备、凝胶的机体反应和体内降解以及药物控释三方面,综述了该给药系统的研究进展,总结了关键技术和科学问题,分析了面临的挑战与解决途径。水凝胶网络的不规则形态和较低的机械强度,其植入后引起的机体炎性反应、组织融合与水分快速流失及这些反应造成的凝胶网络结构和降解速率的个体差异性变化,是控制药物释放的主要困难。通过提高凝胶表面亲水性,降低其表面正电荷,或在其表面修饰抗炎性多肽,可减轻炎性作用、减缓组织融合;通过与亲水性高分子形成共混凝胶或互穿凝胶网络以及共价交联等方式,可提高凝胶强度,保持凝胶网络的空间结构和水分;通过在凝胶表面建立扩散屏障、加强药物和凝胶骨架的相互作用、构建微粒/原位凝胶复合释药系统等技术,可进一步改善药物释放特征。     

Effects of Concentrations on the Transdermal Permeation Enhancing Mechanisms of Borneol: A Coarse-Grained Molecular Dynamics Simulation on Mixed-Bilayer Membranes

Borneol is a natural permeation enhancer that is effective in drugs used in traditional clinical practices as well as in modern scientific research. However, its molecular mechanism is not fully understood. In this study, a mixed coarse-grained model of stratum corneum (SC) lipid bilayer comprised of Ceramide-N-sphingosine (CER NS) 24:0, cholesterol (CHOL) and free fatty acids (FFA) 24:0 (2:2:1) was used to examine the permeation enhancing mechanism of borneol on the model drug osthole. We found two different mechanisms that were dependent on concentrations levels of borneol. At low concentrations, the lipid system maintained a bilayer structure. The addition of borneol made the lipid bilayer loosen and improved drug permeation. The “pull” effect of borneol also improved drug permeation. However, for a strongly hydrophobic drug like osthole, the permeation enhancement of borneol was limited. When most borneol molecules permeated into bilayers and were located at the hydrophobic tail region, the spatial competition effect inhibited drug molecules from permeating deeper into the bilayer. At high concentrations, borneol led to the formation of water pores and long-lived reversed micelles. This improved the permeation of osthole and possibly other hydrophobic or hydrophilic drugs through the SC. Our simulation results were supported by Franz diffusion tests and transmission electron microscope (TEM) experiments.     

Influence of Anionic Surface Charged Biocompatible Dendrimer With a Photosensitizer,Protoporphyrin IX,on Human Red Blood Cells: A Spectroscopic Investigation

A biocompatible anionic dendrimer with carboxylic acid and phenolic hydroxyl functional groups at the surface of every half and full generations was designed by condensing phloroglucinol and succinic acid and its hemolytic effect on red blood cells was studied. The study reveals that the anionic surface charged dendrimer exhibits hemocompatibility and satisfies the reduction of dark toxicity of photosensitizer when loaded inside the nanocarrier, one of the prime requirements for a drug delivery system in photodynamic therapy applications.