Open AccesspH-degradable, bisphosphonate-loaded nanogels attenuate liver fibrosis by repolarization of M2-type macrophages
Author(s) -
Leonard Kaps,
Anne Huppertsberg,
Niklas Choteschovsky,
Adrian Klefenz,
Feyza Durak,
Barbara Schrörs,
Mustafa Diken,
Emma Eichler,
Sebastian Rosigkeit,
Sascha Schmitt,
Christian Leps,
Alicia Schulze,
Friedrich Foerster,
Ernesto Bockamp,
Bruno G. De Geest,
Kaloian Koynov,
HansJoachim Räder,
Stefan Tenzer,
Fédérico Marini,
Detlef Schuppan,
Lutz Nuhn
Publication year - 2022
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.2122310119
Subject(s) - fibrosis , macrophage , cancer research , pharmacology , nanogel , drug delivery , medicine , chemistry , pathology , biochemistry , in vitro , organic chemistry
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.