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      Endocytosis: The Nanoparticle and Submicron Nanocompounds Gateway into the Cell

      review-article
      1 , 2 , 1 , 2 , *
      Pharmaceutics
      MDPI
      nanoparticles, endocytosis, clathrin, caveolin, macropinocytosis

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          Abstract

          Nanoparticles (NPs) and submicron particles are increasingly used as carriers for delivering therapeutic compounds to cells. Their entry into the cell represents the initial step in this delivery process, being most of the nanoparticles taken up by endocytosis, although other mechanisms can contribute to the uptake. To increase the delivery efficiency of therapeutic compounds by NPs and submicron particles is very relevant to understand the mechanisms involved in the uptake process. This review covers the proposed pathways involved in the cellular uptake of different NPs and submicron particles types as well as the role that some of the physicochemical nanoparticle characteristics play in the uptake pathway preferentially used by the nanoparticles to gain access and deliver their cargo inside the cell.

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          Most cited references101

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          Liposomes as nanomedical devices

          Since their discovery in the 1960s, liposomes have been studied in depth, and they continue to constitute a field of intense research. Liposomes are valued for their biological and technological advantages, and are considered to be the most successful drug-carrier system known to date. Notable progress has been made, and several biomedical applications of liposomes are either in clinical trials, are about to be put on the market, or have already been approved for public use. In this review, we briefly analyze how the efficacy of liposomes depends on the nature of their components and their size, surface charge, and lipidic organization. Moreover, we discuss the influence of the physicochemical properties of liposomes on their interaction with cells, half-life, ability to enter tissues, and final fate in vivo. Finally, we describe some strategies developed to overcome limitations of the “first-generation” liposomes, and liposome-based drugs on the market and in clinical trials.
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            Elucidating the mechanism of cellular uptake and removal of protein-coated gold nanoparticles of different sizes and shapes.

            We investigated the mechanism by which transferrin-coated gold nanoparticles (Au NP) of different sizes and shapes entered mammalian cells. We determined that transferrin-coated Au NP entered the cells via clathrin-mediated endocytosis pathway. The NPs exocytosed out of the cells in a linear relationship to size. This was different than the relationship between uptake and size. Furthermore, we developed a mathematical equation to predict the relationship of size versus exocytosis for different cell lines. These studies will provide guidelines for developing NPs for imaging and drug delivery applications, which will require "controlling" NP accumulation rate. These studies will also have implications in determining nanotoxicity.
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              Endosomal escape pathways for delivery of biologicals.

              Despite continuous improvements in delivery systems, the development of methods for efficient and specific delivery of targeted therapeutic agents still remains an issue in biological treatments such as protein and gene therapy. The endocytic pathway is the major uptake mechanism of cells and any biological agents, such as DNA, siRNA and proteins. These agents become entrapped in endosomes and are degraded by specific enzymes in the lysosome. Thus, a limiting step in achieving an effective biological based therapy is to facilitate the endosomal escape and ensure cytosolic delivery of the therapeutics. Bacteria and viruses are pathogens which use different mechanisms to penetrate the membranes of their target cells and escape the endosomal pathway. Different mechanisms such as pore formation in the endosomal membrane, pH-buffering effect of protonable groups and fusion into the lipid bilayer of endosomes have been proposed to facilitate the endosomal escape. Several viral and bacterial proteins have been identified that are involved in this process. In addition, chemical agents and photochemical methods to rupture the endosomal membrane have been described. New synthetic biomimetic peptides and polymers with high efficacy in facilitating the endosomal escape, low pathogenicity and toxicity have been developed. Each strategy has different characteristics and challenges for designing the best agents and techniques to facilitate the endosomal escape are ongoing. In this review, several mechanisms and agents which are involved in endosomal escape are introduced. Copyright © 2010 Elsevier B.V. All rights reserved.
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                Author and article information

                Journal
                Pharmaceutics
                Pharmaceutics
                pharmaceutics
                Pharmaceutics
                MDPI
                1999-4923
                17 April 2020
                April 2020
                : 12
                : 4
                : 371
                Affiliations
                [1 ]Unidad Asociada Neurodeath, Universidad de Castilla-La Mancha, 02006 Albacete, Spain; dario.manzanares@ 123456uclm.es
                [2 ]CIBERNED, Instituto de Salud Carlos III, 28031 Madrid, Spain
                Author notes
                Author information
                https://orcid.org/0000-0001-8928-3681
                Article
                pharmaceutics-12-00371
                10.3390/pharmaceutics12040371
                7238190
                32316537
                1d012834-092c-46f1-8e6d-e64183b6dccd
                © 2020 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 23 March 2020
                : 15 April 2020
                Categories
                Review

                nanoparticles,endocytosis,clathrin,caveolin,macropinocytosis

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