title: Specific uptake mechanisms of well-tolerated thermoresponsive polyglycerol-based nanogels in antigen-presenting cells of the skin.
abstract: Engineered nanogels are of high value for a targeted and controlled transport of compounds due to the ability to change their chemical properties by external stimuli. As it has been indicated that nanogels possess a high ability to penetrate the stratum corneum, it cannot be excluded that nanogels interact with dermal dendritic cells, especially in diseased skin. In this study the potential crosstalk of the thermoresponsive nanogels (tNGs) with the dendritic cells of the skin was investigated with the aim to determine the immunotoxicological properties of the nanogels. The investigated tNGs were made of dendritic polyglycerol (dPG) and poly(glycidyl methyl ether-co-ethyl glycidyl ether) (p(GME-co-EGE)), as polymer conferring thermoresponsive properties. Although the tNGs were taken up, they displayed neither cytotoxic and genotoxic effects nor any induction of reactive oxygen species in the tested cells. Interestingly, specific uptake mechanisms of the tNGs by the dendritic cells were depending on the nanogels cloud point temperature (Tcp), which determines the phase transition of the nanoparticle. The study points to caveolae-mediated endocytosis as being the major tNGs uptake mechanism at 37°C, which is above the Tcp of the tNGs. Remarkably, an additional uptake mechanism, beside caveolae-mediated endocytosis, was observed at 29°C, which is the Tcp of the tNGs. At this temperature, which is characterized by two different states of the tNGs, macropinocytosis was involved as well. In summary, our study highlights the impact of thermoresponsivity on the cellular uptake mechanisms which has to be taken into account if the tNGs are used as a drug delivery system.
authors.affiliation: Institute of Nutritional Science, University of Potsdam, Potsdam, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Edlich
authors.affiliation: Institute of Nutritional Science, University of Potsdam, Potsdam, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Gerecke
authors.affiliation: Institute of Chemistry and Biochemistry, Freie Universität Berlin, Berlin, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Giulbudagian
authors.affiliation: Institute of Chemistry and Biochemistry, Freie Universität Berlin, Berlin, Germany.
authors.forename: Falko
authors.initials: F
authors.lastname: Neumann
authors.affiliation: Institute of Pharmacy, Freie Universität Berlin, Berlin, Germany.
authors.forename: Sarah
authors.initials: S
authors.lastname: Hedtrich
authors.affiliation: Institute of Pharmacy, Freie Universität Berlin, Berlin, Germany.
authors.forename: Monika
authors.initials: M
authors.lastname: Schäfer-Korting
authors.affiliation: Institute of Biomaterial Science and Berlin-Brandenburg Center for Regenerative Therapies, Helmholtz-Zentrum Geesthacht, Teltow, Germany.
authors.forename: Nan
authors.initials: N
authors.lastname: Ma
authors.affiliation: Institute of Chemistry and Biochemistry, Freie Universität Berlin, Berlin, Germany.
authors.forename: Marcelo
authors.initials: M
authors.lastname: Calderon
authors.affiliation: Institute of Nutritional Science, University of Potsdam, Potsdam, Germany. Electronic address: kleuser@uni-potsdam.de.
authors.forename: Burkhard
authors.initials: B
authors.lastname: Kleuser
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000378:metabolism*; D021941:Caveolae / Q000378:metabolism; D002460:Cell Line; D003713:Dendritic Cells / Q000378:metabolism; D004337:Drug Carriers / Q000378:metabolism; D016503:Drug Delivery Systems / Q000379:methods; D004705:Endocytosis / Q000502:physiology; D004852:Epoxy Compounds / Q000378:metabolism; D005990:Glycerol / Q000378:metabolism*; D008738:Methyl Ethers / Q000378:metabolism; D051379:Mice; D000080385:Nanogels; D053758:Nanoparticles / Q000378:metabolism; D011092:Polyethylene Glycols / Q000378:metabolism*; D011094:Polyethyleneimine / Q000378:metabolism*; D011108:Polymers / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D012867:Skin / Q000378:metabolism*; D012869:Skin Absorption / Q000502:physiology; D013696:Temperature
chemical_list: D004337:Drug Carriers; D004852:Epoxy Compounds; D008738:Methyl Ethers; D000080385:Nanogels; D011108:Polymers; D017382:Reactive Oxygen Species; C020344:glycidyl ethers; C413692:polyethylene glycol polyethyleneimine nanogel; C043941:polyglycerol; D011092:Polyethylene Glycols; D011094:Polyethyleneimine; D005990:Glycerol
keywords: Dendritic cells; Drug delivery systems; Nanogel; Nanoparticle; Nanoparticle uptake; Nanotoxicology