pH-degradable, bisphosphonate-loaded nanogels attenuate liver fibrosis by repolarization of M2-type macrophages

Author:

Kaps Leonard12ORCID,Huppertsberg Anne3,Choteschovsky Niklas1,Klefenz Adrian1ORCID,Durak Feyza4ORCID,Schrörs Babara4ORCID,Diken Mustafa4,Eichler Emma1ORCID,Rosigkeit Sebastian1,Schmitt Sascha3,Leps Christian5,Schulze Alicia6ORCID,Foerster Friedrich12ORCID,Bockamp Ernesto1ORCID,De Geest Bruno G.7ORCID,Koynov Kaloian3ORCID,Räder Hans-Joachim3,Tenzer Stefan5ORCID,Marini Federico6,Schuppan Detlef18,Nuhn Lutz3ORCID

Affiliation:

1. Institute of Translational Immunology and Research Center for Immune Therapy, University Medical Center, Johannes Gutenberg-University Mainz, 55131 Mainz, Germany

2. Department of Internal Medicine I, University Medical Center, Johannes Gutenberg-University Mainz, 55131 Mainz, Germany

3. Max Planck Institute for Polymer Research, 55128 Mainz, Germany

4. TRON-Translational Oncology gGmbH, University Medical Center, Johannes Gutenberg-University Mainz, 55131 Mainz, Germany

5. Institute for Immunology, University Medical Center, Johannes Gutenberg-University Mainz, 55131 Mainz, Germany

6. Institute of Medical Biostatistics, Epidemiology and Informatics, University Medical Center, Johannes Gutenberg-University Mainz, 55131 Mainz, Germany

7. Department of Pharmaceutics and Cancer Research Institute Ghent, Ghent University, 9000 Ghent, Belgium

8. Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215

Abstract

Significance Fibrosis is a consequence of most chronic liver diseases, but currently no approved antifibrotic treatment is available. M2-type macrophages drive fibrosis progression and prevent regression, even when effective causal therapies have been employed. M2-type macrophages activate a cascade of fibrogenic effector cells and can prevent removal of excess scar tissue. To switch these profibrogenic M2 to fibrolytic (regenerative) macrophages, we developed a pH-degradable, nanogel-based delivery system which can be covalently functionalized with the macrophage-repolarizing bisphosphonate alendronate. The nanogels efficiently deliver the clinically approved drug into hepatic nonparenchymal cells after intravenous administration. They do not eliminate macrophages but repolarize their phenotype and subsequently block fibrosis progression. This approach establishes a nanotherapeutic delivery platform to treat further M2-type macrophage-driven diseases, including cancer.

Funder

Deutsche Forschungsgemeinschaft

Max Planck Graduate Center with the Johannes Gutenberg-University Mainz

Publisher

Proceedings of the National Academy of Sciences

Subject

Multidisciplinary

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