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

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.

Influence of Advanced Organ Support (ADVOS) on Cytokine Levels in Patients with Acute-on-Chronic Liver Failure (ACLF)

“…Because cytokines are the major mediators of inflammation, we sought to clarify the relevance of previously assessed cytokines in ACLF through Ingenuity pathway analysis (IPA ® ) [ 5 , 14 ]. The key ACLF cytokines IL-10, IL-6, and TNF-α were linked to the inflammasome pathway, which is known to be a relevant pathway for sustaining systemic inflammation in ACLF.…”

“…One of the hallmarks of ACLF is hyperinflammation, which is mainly driven by inflammatory cytokines [ 33 ]. We performed an IPA ® -powered network analysis based on curated experimental data to determine the effects of the quantified cytokines on the ACLF inflammasome pathway [ 14 ]. We selected this pathway because of its relevance for hyperinflammation in ACLF [ 6 ].…”

“…IPA ® predicts (de)activation of a disease’s related pathways based on a comprehensive database derived from experimental data [ 14 ]. Selected cytokines were linked to the inflammasome pathway, which is known to be a major driver of hyperinflammation in ACLF [ 6 ].…”

The Role of Macrophages in Liver Fibrosis: New Therapeutic Opportunities

“…Mortality from CLDs in the UK has increased by over 400% since 1970 [ 37 ]. In addition to mortality, CLDs lead to a significant impairment of patients’ quality of life [ 35 ], as it is associated with life-threatening complications, including liver failure, infections, portal hypertension with esophageal and variceal bleeding or ascites, and a 2 to 6% annual incidence of primary liver cancer [ 38 ].…”

“…L. Kaps et al, developed pH-degradable, squaric ester-based nanogel carries system for the delivery of the bisphosphonate, an agent that reprograms profibrotic M2- toward antifibrotic M1-macrophages. They demonstrated that this approach potently prevented liver progression in vivo [ 38 ].…”