New synthetic aminooxy lipid was designed and synthesized as a building block for the formulation of functionalised nanoliposomes (presenting onto the outer surface of aminooxy groups) by microfluidic mixing. Orthogonal binding of cellular mannan (Candida glabrata (CCY 26-20-1) onto the outer surface of functionalised nanoliposomes was modified by orthogonal binding of reducing termini of mannans to oxime lipids via a click chemistry reaction based on aminooxy coupling (oxime ligation). The aminooxy lipid was proved as a suitable active component for preparation of functionalised nanoliposomes by the microfluidic mixing method performed with the instrument NanoAssemblrTM. This "on-chip technology" can be easily scaled-up. The structure of mannan-liposomes was visualized by transmission and scanning electron microscopy, including immunogold staining of recombinant mannan receptor bound onto mannosylated-liposomes. The observed structures are in a good correlation with data obtained by DLS, NTA, and TPRS methods. In vitro experiments on human and mouse dendritic cells demonstrate selective internalisation of fluorochrome-labelled mannan-liposomes and their ability to stimulate DC comparable to lipopolysaccharide. We describe a potentially new drug delivery platform for mannan receptor-targeted antimicrobial drugs as well as for immunotherapeutics. Furthermore, the platform based on mannans bound orthogonally onto the surface of nanoliposomes represents a self-adjuvanted carrier for construction of liposome-based recombinant vaccines for both systemic and mucosal routes of administration.

APIGENEX s r o Poděbradská 173 5 Prague 9 190 00 Czech Republic

Department of Chemistry of Natural Compounds University of Chemistry and Technology Technická 5 166 28 Prague 6 Czech Republic

Department of Immunochemistry of Glycoconjugates Immunology and Cell Culture Laboratory Institute of Chemistry Center for Glycomics Slovak Academy of Sciences Dubravska cesta 9 845 38 Bratislava Slovakia

Department of Immunology and Institute of Molecular and Translational Medicine Faculty of Medicine and Dentistry Palacky University Olomouc Hněvotínská 3 775 15 Olomouc Czech Republic

Department of Pharmacology and Immunotherapy Veterinary Research Institute v v i Hudcova 70 621 00 Brno Czech Republic

Division of Neurosciences Biomedical Center Martin Jessenius Faculty of Medicine in Martin Comenius University Malá Hora 10701 4A 036 01 Martin Slovakia

Malvern Instruments Great Malvern UK

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$a Bartheldyová, Eliška $u Department of Pharmacology and Immunotherapy, Veterinary Research Institute, v.v.i., Hudcova 70, 621 00 Brno, Czech Republic.

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$a N-Oxy lipid-based click chemistry for orthogonal coupling of mannan onto nanoliposomes prepared by microfluidic mixing: Synthesis of lipids, characterisation of mannan-coated nanoliposomes and in vitro stimulation of dendritic cells / $c E. Bartheldyová, P. Turánek Knotigová, K. Zachová, J. Mašek, P. Kulich, R. Effenberg, D. Zyka, F. Hubatka, J. Kotouček, H. Čelechovská, R. Héžová, A. Tomečková, E. Mašková, M. Fojtíková, S. Macaulay, P. Bystrický, L. Paulovičová, E. Paulovičová, L. Drož, M. Ledvina, M. Raška, J. Turánek,

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$a New synthetic aminooxy lipid was designed and synthesized as a building block for the formulation of functionalised nanoliposomes (presenting onto the outer surface of aminooxy groups) by microfluidic mixing. Orthogonal binding of cellular mannan (Candida glabrata (CCY 26-20-1) onto the outer surface of functionalised nanoliposomes was modified by orthogonal binding of reducing termini of mannans to oxime lipids via a click chemistry reaction based on aminooxy coupling (oxime ligation). The aminooxy lipid was proved as a suitable active component for preparation of functionalised nanoliposomes by the microfluidic mixing method performed with the instrument NanoAssemblrTM. This "on-chip technology" can be easily scaled-up. The structure of mannan-liposomes was visualized by transmission and scanning electron microscopy, including immunogold staining of recombinant mannan receptor bound onto mannosylated-liposomes. The observed structures are in a good correlation with data obtained by DLS, NTA, and TPRS methods. In vitro experiments on human and mouse dendritic cells demonstrate selective internalisation of fluorochrome-labelled mannan-liposomes and their ability to stimulate DC comparable to lipopolysaccharide. We describe a potentially new drug delivery platform for mannan receptor-targeted antimicrobial drugs as well as for immunotherapeutics. Furthermore, the platform based on mannans bound orthogonally onto the surface of nanoliposomes represents a self-adjuvanted carrier for construction of liposome-based recombinant vaccines for both systemic and mucosal routes of administration.

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$a Turánek Knotigová, Pavlína $u Department of Pharmacology and Immunotherapy, Veterinary Research Institute, v.v.i., Hudcova 70, 621 00 Brno, Czech Republic.

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$a Zachová, Kateřina $u Department of Immunology and Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University Olomouc, Hněvotínská 3, 775 15 Olomouc, Czech Republic.

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$a Mašek, Josef $u Department of Pharmacology and Immunotherapy, Veterinary Research Institute, v.v.i., Hudcova 70, 621 00 Brno, Czech Republic.

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$a Kulich, Pavel $u Department of Pharmacology and Immunotherapy, Veterinary Research Institute, v.v.i., Hudcova 70, 621 00 Brno, Czech Republic.

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$a Effenberg, Roman $u Department of Chemistry of Natural Compounds, University of Chemistry and Technology, Technická 5, 166, 28 Prague 6, Czech Republic.

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$a Zyka, Daniel $u APIGENEX s.r.o., Poděbradská 173/5, Prague 9, 190 00, Czech Republic.

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$a Kotouček, Jan $u Department of Pharmacology and Immunotherapy, Veterinary Research Institute, v.v.i., Hudcova 70, 621 00 Brno, Czech Republic. $7 xx0279654

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$a Paulovičová, Lucia $u Department of Immunochemistry of Glycoconjugates, Immunology & Cell Culture Laboratory, Institute of Chemistry, Center for Glycomics Slovak Academy of Sciences, Dubravska cesta 9, 845 38 Bratislava, Slovakia.

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$a Paulovičová, Ema $u Department of Immunochemistry of Glycoconjugates, Immunology & Cell Culture Laboratory, Institute of Chemistry, Center for Glycomics Slovak Academy of Sciences, Dubravska cesta 9, 845 38 Bratislava, Slovakia. Electronic address: ema.paulovicova@savba.sk.

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$a Ledvina, Miroslav $u Department of Chemistry of Natural Compounds, University of Chemistry and Technology, Technická 5, 166, 28 Prague 6, Czech Republic. Electronic address: miroslav.ledvina@vscht.cz.

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$a Raška, Milan $u Department of Pharmacology and Immunotherapy, Veterinary Research Institute, v.v.i., Hudcova 70, 621 00 Brno, Czech Republic; Department of Immunology and Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University Olomouc, Hněvotínská 3, 775 15 Olomouc, Czech Republic. Electronic address: raskamil@uab.edu.

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$a Turánek, Jaroslav $u Department of Pharmacology and Immunotherapy, Veterinary Research Institute, v.v.i., Hudcova 70, 621 00 Brno, Czech Republic. Electronic address: turanek@vri.cz.

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