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Endocytosis: the Nanoparticle and Submicron Nanocompounds Gateway Into the Cell

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pharmaceutics Review Endocytosis: The Nanoparticle and Submicron Nanocompounds Gateway into the Cell Darío Manzanares 1,2 and Valentín Ceña 1,2,* 1 Unidad Asociada Neurodeath, Universidad de Castilla-La Mancha, 02006 Albacete, Spain; [email protected] 2 CIBERNED, Instituto de Salud Carlos III, 28031 Madrid, Spain * Correspondence: [email protected] Received: 23 March 2020; Accepted: 15 April 2020; Published: 17 April 2020 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. Keywords: nanoparticles; endocytosis; clathrin; caveolin; macropinocytosis 1. Introduction Nanomedicine has become one of the most rapidly growing areas of research in the biomedical field during the last years. Nanoparticles (NPs) and submicron particles (named both from this point as NPs to abbreviate) are defined as materials with nanometric sizes (1–100 and 100–1000 nm, respectively) that interact with biological systems in an unusual way because of their high surface to volume ratio. This property, combined with the possibility of modifying their peripheral chemical groups to achieve multitasking properties, provides NPs compounds with a very high potential for diagnostic and therapeutic applications in nanomedicine. Thus, they offer the potential for a more selective and accurate treatment in a huge variety of pathologies including infectious, auto-immune and inflammatory processes, cancer or neurodegenerative diseases, among many others, by acting as carriers of drugs enabling a targeted delivery of therapeutic agents (from small drugs to genetic material) at the cellular or subcellular level, or by the therapeutic properties of the NP itself. In addition, NPs have also potential usefulness in diagnostics which might lead to the improvement of many of currently performed medical procedures [1,2]. The initial interaction between NPs and their cargo with the target cell involves uptake into the cell, being the internalization pathway very relevant to achieve the intended effect. Nanoparticles can gain access to the cell interior through simple diffusion or translocation, an energy-independent process that depends on the NP concentration gradient, but also on other factors such as its liposolubility [1]. However, the most common mechanism used by NPs to enter the cells is an energy-dependent process named endocytosis that has been described as the uptake of substances from the extracellular environment by vesicles generated from the cell plasma membrane [3]. The knowledge of the uptake route is important because, depending on it, the fate of the NP can be different, being useful or not for certain purposes. For instance, transcytosis (in which a vesicle Pharmaceutics 2020, 12, 371; doi:10.3390/pharmaceutics12040371 www.mdpi.com/journal/pharmaceutics Pharmaceutics 2020, 12, 371 2 of 22 Pharmaceutics 2020, 12, x FOR PEER REVIEW 2 of 20 travelstravels across a a cell) cell) is is very very important important in in certain certain pr processesocesses such such as asthe the gastrointestinal gastrointestinal absorption absorption for fororal oral preparations preparations or orto tobe be incorporated incorporated into into the the blood blood stream. stream. In In this case, caveolin-mediatedcaveolin-mediated endocytosis (CVME)(CVME) plays plays the the main main role. role. In In addition, addition, many many therapeutic therapeutic compounds compounds can can be be designed designed to arriveto arrive to specificto specific cellular cellular organelles organelles where where they canthey play can a therapeuticplay a therapeutic role, being role, the being uptake the pathway uptake determinantpathway determinant in their intracellular in their intracellular fate. This fate. is the Th caseis is forthe NPs case taken for NPs up taken by CVME, up by which CVME, involves which endoplasmicinvolves endoplasmic reticulum reticulum and Golgi and complex, Golgi and complex, could beand useful could to be target useful those to target organelles those and organelles to carry certainand to drugscarry there.certain In drugs addition, there. the In uptake addition, route the can uptake also leadroute to can less endosomalalso lead to degradation less endosomal and largerdegradation cargo release and larger to the cargo cytosol release depending to the cytoso on thel NP depending employed on and the the NP cell employed type. Thus, and CVMEthe cell seems type. toThus, avoid CVME the endo-lysosomal seems to avoid systemthe endo-lysosomal in some cell types system while in some other cell authors types report while that other macropinosomes authors report arethat more macropinosomes likely to liberate are theirmore contentlikely to without liberate lysosomal their content degradation without lysosomal [4]. degradation [4]. InIn addition,addition, NPsNPs propertiesproperties can have a greatgreat influenceinfluence inin thethe endosomalendosomal escapeescape beforebefore fusingfusing lysosomes.lysosomes. So, So, there there are are several several mechanisms mechanisms by by which which NPs NPs can can escape escape the the endosomes endosomes including: including: a) (a)proton proton sponge sponge effect effect which which involves involves un-protonate un-protonatedd amine amine groups groups of ofNPs NPs absorbing absorbing protons protons due due to toendosome endosome acidification, acidification, triggering triggering the the entrance entrance of of Cl- Cl- ions ions and, and, consequently, consequently, water water by osmosis, causingcausing thethe endosome endosome rupture, rupture, (b) b) umbrella umbrella eff ecteffe whichct which involves involves amine amine protonation protonation leading leading to charge to repulsions,charge repulsions, which would which expandwould expand the structure the structure leading leading to endosomal to endosomal rupture, rupture, (c) direct c) fusion direct offusion NPs withof NPs the with endosome the endosome membrane membrane and formation and formation of pores in of the pores endosome in the surfaceendosome due surface to the induction due to the of membraneinduction of stress membrane and internal stress membraneand internal tension membrane [5]. tension [5]. This article presents anan overview ofof the pathways by which the didifferentfferent typestypes ofof NPs gain access toto thethe cellcell interior.interior. 2. Classification of the Endocytic Pathways 2. Classification of the Endocytic Pathways There are different mechanisms of endocytosis (Figure1) that are generally classified as follows: There are different mechanisms of endocytosis (Figure 1) that are generally classified as follows: Figure 1.1. MainMain energy-dependent uptake pathwayspathways ofof thethe cell.cell. Macropinocytosis formsforms macropinosomes thatthat could could finally finally join join the the early earl endosomes.y endosomes. Clathrin-mediated Clathrin-mediated endocytosis endocytosis (CME) (CME) and caveolinand caveolin mediated mediated endocytosis endocytosis (CVME) (CVME) are the mainare the receptor-mediated main receptor-mediated endocytosis endocytosis (RME) processes. (RME) Onprocesses. the other On hand, the other other hand, endocytic other RMEendocytic mechanisms RME mechanisms as flotillin, as ARF6, flotillin RhoA,, ARF6, orCDC42 RhoA, or mediated CDC42 endocytosismediated endocytosis are also present are also in thepresen cell.t in The the final cell. fate The of final endosome fate of vesiclesendosome is to vesicles fuse with is to lysosomes. fuse with lysosomes. 2.1. Phagocytosis 2.1. Phagocytosis Phagocytosis consists in the uptake by the cell of opsonized particulate substances and solutes by vesiclesPhagocytosis with a size consists in the micrometer in the uptake range by that the incorporatecell of opsonized large plasmaparticulate membrane substances surface and areas solutes [3]. by vesicles with a size in the micrometer range that incorporate large plasma membrane surface areas [3]. Since phagocytosis is barely used as a mechanism for NPs uptake, it will not be described in detail in this review. Pharmaceutics 2020, 12, 371 3 of 22 Since phagocytosis is barely used as a mechanism for NPs uptake, it will not be described in detail in Pharmaceutics 2020, 12, x FOR PEER REVIEW 3 of 20 this review. 2.2.2.2. Pinocytosis PinocytosisPinocytosis involves the uptake of fluidsfluids containingcontaining solutessolutes andand particlesparticles byby vesiclesvesicles ofof smallersmaller sizesize thanthan thosethose generatedgenerated duringduring phagocytosis.phagocytosis. This endocytic mechanism can be classifiedclassified inin macropinocytosismacropinocytosis andand receptor-mediatedreceptor-mediated endocytosisendocytosis (RME).(RME). 2.2.1.2.2.1. Macropinocytosis MacropinocytosisMacropinocytosis allows the uptake of materialmaterial throughthrough largelarge vacuoles,vacuoles,
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