title: Orthogonal Click Conjugation to the Liposomal Surface Reveals the Stability of the Lipid Anchorage as Crucial for Targeting.
abstract: Synthetic access to multiple surface decorations are a bottleneck in the development of liposomes for receptor mediated targeting. This opens a complex multiparameter space, exploration of which is severely limited in terms of sample numbers and turnaround times. Here, we unlock this technological barrier by a combination of a milligram-scale liposome formulation using dual centrifugation and orthogonal click chemistry on the liposomal surface. Application of these techniques to conceptually new amphiphilic compounds, which feature norbornene and alkyne groups at the apex of sterically stabilizing, hyperbranched polyglycerol moieties, revealed a particular influence of the membrane anchor of functional amphiphiles. Folic acid residues clicked to cholesterol-based amphiphiles were inefficient in folate-mediated cell targeting, while dialkyl-anchored amphiphiles remained stable in the liposomal membrane and imparted efficient targeting properties. These findings are of specific importance considering the popularity of cholesterol as a lipophilic anchor.
authors.affiliation: Institute of Pharmacy and Biochemistry, Johannes Gutenberg-University Mainz, Staudingerweg 5, 55128, Mainz, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Fritz
authors.affiliation: Institute of Pharmacy and Biochemistry, Johannes Gutenberg-University Mainz, Staudingerweg 5, 55128, Mainz, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Voigt
authors.affiliation: Institute of Organic Chemistry, Johannes Gutenberg-University Mainz, Duesbergweg 10-14, 55128, Mainz, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Worm
authors.affiliation: Institute of Pharmacy and Biochemistry, Johannes Gutenberg-University Mainz, Staudingerweg 5, 55128, Mainz, Germany.|Max Planck Institute for Polymer Research, Ackermannweg 10, 55128, Mainz, Germany.
authors.forename: Inka
authors.initials: I
authors.lastname: Negwer
authors.affiliation: Institute of Organic Chemistry, Johannes Gutenberg-University Mainz, Duesbergweg 10-14, 55128, Mainz, Germany.|Graduate School MAINZ, Johannes Gutenberg-University Mainz, Staudingerweg 9, 55128, Mainz, Germany.
authors.forename: Sophie S
authors.initials: SS
authors.lastname: Müller
authors.affiliation: Institute of Nuclear Chemistry, Johannes Gutenberg-University Mainz, Fritz Strassmann Weg 2, 55128, Mainz, Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Kettenbach
authors.affiliation: Department of Nuclear Medicine, Hannover Medical School, Carl-Neuberg-Str.1, 30625, Hannover, Germany.
authors.forename: Tobias L
authors.initials: TL
authors.lastname: Ross
authors.affiliation: Institute of Nuclear Chemistry, Johannes Gutenberg-University Mainz, Fritz Strassmann Weg 2, 55128, Mainz, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Roesch
authors.affiliation: Max Planck Institute for Polymer Research, Ackermannweg 10, 55128, Mainz, Germany.
authors.forename: Kaloian
authors.initials: K
authors.lastname: Koynov
authors.affiliation: Institute of Organic Chemistry, Johannes Gutenberg-University Mainz, Duesbergweg 10-14, 55128, Mainz, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Frey
authors.affiliation: Institute of Pharmacy and Biochemistry, Johannes Gutenberg-University Mainz, Staudingerweg 5, 55128, Mainz, Germany. m.helm@uni-mainz.de.
authors.forename: Mark
authors.identifier: http://orcid.org/0000-0002-0154-0928
authors.initials: M
authors.lastname: Helm
mesh_terms: D002784:Cholesterol / Q000097:blood / Q000737:chemistry*; D057930:Click Chemistry; D005492:Folic Acid / Q000737:chemistry*; D005990:Glycerol / Q000737:chemistry*; D006801:Humans; D008055:Lipids / Q000737:chemistry*; D008081:Liposomes / Q000737:chemistry*; D011108:Polymers / Q000737:chemistry*
chemical_list: D008055:Lipids; D008081:Liposomes; D011108:Polymers; C043941:polyglycerol; D005492:Folic Acid; D002784:Cholesterol; D005990:Glycerol
keywords: click chemistry; drug delivery; folic acid; liposomes; polyglycerol