Mechanisms of selective monocyte targeting by liposomes functionalized with a cationic, arginine-rich lipopeptide. (May 2022)

• Record Type: Journal Article
• Authors: Münter, Rasmus; Bak, Martin; Christensen, Esben; Kempen, Paul J.; Larsen, Jannik B.; Kristensen, Kasper; Parhamifar, Ladan; Andresen, Thomas L.
• Is Part Of: Acta biomaterialia. Volume 144(2022)
• Page Start: 96
• Page End: 108
• Publication Date: 2022-05
• Subjects: Cationic liposome -- Immunotherapy -- CD14 -- Complement -- Monocyte; Biomedical materials -- Periodicals; 610.28
• DOI: 10.1016/j.actbio.2022.03.029
• Languages: English
• ISSNs: 1742-7061

Abstract

Abstract: Stimulation of monocytes with immunomodulating agents can harness the immune system to treat a long range of diseases, including cancers, infections and autoimmune diseases. To this end we aimed to develop a monocyte-targeting delivery platform based on cationic liposomes, which can be utilized to deliver immunomodulators and thus induce monocyte-mediated immune responses while avoiding off-target side-effects. The cationic liposome design is based on functionalizing the liposomal membrane with a cholesterol-anchored tri-arginine peptide (TriArg). We demonstrate that TriArg liposomes can target monocytes with high specificity in both human and murine blood and that this targeting is dependent on the content of TriArg in the liposomal membrane. In addition, we show that the mechanism of selective monocyte targeting involves the CD14 co-receptor, and selectivity is compromised when the TriArg content is increased, resulting in complement-mediated off-target uptake in granulocytes. The presented mechanistic findings of uptake by peripheral blood leukocytes may guide the design of future drug delivery systems utilized for immunotherapy. Statement of significance: Monocytes are attractive targets for immunotherapies of cancers, infections and autoimmune diseases. Specific delivery of immunostimulatory drugs to monocytes is typically achieved using ligand-targeted drug delivery systems, but a simpler approach is to target monocytes using cationic liposomes. To achieve this, however, a deep understanding of the mechanisms governing the interactions of cationic liposomes with monocytes and other leukocytes is required. We here investigate these interactions using liposomes incorporating a cationic arginine-rich lipopeptide. We demonstrate that monocyte targeting can be achieved by fine-tuning the lipopeptide content in the liposomes. Additionally, we reveal that the CD14 receptor is involved in the targeting process, whereas the complement system is not. These mechanistic findings are critical for future design of monocyte-targeting liposomal therapies. Graphical abstract: Image, graphical abstract