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Eur J Pharm Biopharm. 2018 Dec;133:138-150. doi: 10.1016/j.ejpb.2018.09.017. Epub 2018 Sep 25.

Sortaggable liposomes: Evaluation of reaction conditions for single-domain antibody conjugation by Sortase-A and targeting of CD11b+ myeloid cells.

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Merck KGaA, Frankfurter Str. 250, 64293 Darmstadt, Germany; Department of Pharmaceutics and Biopharmaceutics, Kiel University, Grasweg 9a, 24118 Kiel, Germany. Electronic address:
BioMed X GmbH, Im Neuenheimer Feld 583, 69120 Heidelberg, Germany.
Merck KGaA, Frankfurter Str. 250, 64293 Darmstadt, Germany.
Department of Pharmaceutics and Biopharmaceutics, Kiel University, Grasweg 9a, 24118 Kiel, Germany.


Active targeting with ligand coated liposomal drug delivery systems is a means to increase the therapeutic index of drugs. Stable ligand coating requires bilayer anchorage of the commonly proteinaceous ligands and hence a conjugation of lipid structures towards amino acids. This often leads to heterogeneous reaction products especially when chemical coupling methods are employed. Chemoenzymatic Sortase-A mediated transpeptidation (sortagging) is a useful tool to avoid this protein heterogeneity through its site-specific, bioorthogonal ligation mechanism. Manufacturing of such sortaggable, pentaglycine modified liposomes was developed by adaption of a scalable solvent injection technique. The pentaglycine liposomes were prepared with different degrees of PEGylation and steric accessibility of the pentaglycine motif. Comparable hydrodynamic diameters (146-188 nm) of the different formulations were obtained after a flow rate screening. The sortagging reactivity of a single-domain antibody (VHH) towards the pentaglycine liposomes was strongly dependent on the steric accessibility of the pentaglycine nucleophile. Adjusting the pentaglycine to ligand ratio improved conversion rates up to 80%. The liposome bound VHH was accessible for its soluble antigen as shown by a chromatography-based binding assay. Mono- and granulocytes could be selectively targeted in vitro by conjugation of BMX1, a VHH directed towards human myeloid cell surface marker CD11b. Confocal microscopy revealed intracellular localization of the targeted liposomes. The developability of those pentaglycine liposomes as well as their proof of principle for targeted drug delivery shows their potential for further investigation, for example as delivery platform for diagnostics or drugs into the tumor microenvironment.


Bioconjugation; Immunoliposomes; Single-domain antibodies; Sortagging; Sortase-A; Targeted drug delivery

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