Liver-targeted nanoparticles delivering nitric oxide reduce portal hypertension in cirrhotic rats.

Nitric oxide (NO) is a small vasodilator playing a key role in the pathogenesis of portal hypertension. Here, we assessed the potential therapeutic effect of a NO donor targeted to the liver by poly(beta-amino ester) nanoparticles (pBAE NPs) in experimental cirrhosis. Retinol-functionalized NO donor pBAE NPs (Ret pBAE NPs) were synthetized with the aim of actively targeting the liver. Administration of Ret pBAE NPs resulted in uptake and transfection by the liver and spleen. NPs were not found in other organs or the systemic circulation. Treatment with NO donor Ret pBAE NPs (30 mg/ kg body weight) significantly decreased aspartate aminotransferase, lactate dehydrogenase and portal pressure (9.75 ± 0.64 mmHg) compared to control NPs (13.4 ± 0.53 mmHg) in cirrhotic rats. There were no effects on mean arterial pressure and cardiac output. Liver-targeted NO donor NPs reduced collagen fibers and steatosis, activation of hepatic stellate cells and mRNA expression of profibrogenic and proinflammatory genes. Finally, Ret pBAE NPs displayed efficient transfection in human liver slices. Overall, liver-specific NO donor NPs effectively target the liver and mitigated inflammation and portal hypertension in cirrhotic rats. The use of Ret pBAE may prove to be an effective therapeutic strategy to treat advanced liver disease.

Atherosclerotic plaque development in mice is enhanced by myeloid ZEB1 downregulation.

Accumulation of lipid-laden macrophages within the arterial neointima is a critical step in atherosclerotic plaque formation. Here, we show that reduced levels of the cellular plasticity factor ZEB1 in macrophages increase atherosclerotic plaque formation and the chance of cardiovascular events. Compared to control counterparts (Zeb1WT/ApoeKO), male mice with Zeb1 ablation in their myeloid cells (Zeb1∆M/ApoeKO) have larger atherosclerotic plaques and higher lipid accumulation in their macrophages due to delayed lipid traffic and deficient cholesterol efflux. Zeb1∆M/ApoeKO mice display more pronounced systemic metabolic alterations than Zeb1WT/ApoeKO mice, with higher serum levels of low-density lipoproteins and inflammatory cytokines and larger ectopic fat deposits. Higher lipid accumulation in Zeb1∆M macrophages is reverted by the exogenous expression of Zeb1 through macrophage-targeted nanoparticles. In vivo administration of these nanoparticles reduces atherosclerotic plaque formation in Zeb1∆M/ApoeKO mice. Finally, low ZEB1 expression in human endarterectomies is associated with plaque rupture and cardiovascular events. These results set ZEB1 in macrophages as a potential target in the treatment of atherosclerosis.

RNF41 orchestrates macrophage-driven fibrosis resolution and hepatic regeneration.

Hepatic inflammation is a common trigger of chronic liver disease. Macrophage activation is a predictive parameter for survival in patients with cirrhosis. Ring finger protein 41 (RNF41) negatively regulates proinflammatory cytokines and receptors; however, the precise involvement of macrophage RNF41 in liver cirrhosis remains unknown. Here, we sought to understand how RNF41 dictates macrophage fate in hepatic fibrosis and repair within the inflammatory milieu. We found that RNF41 expression is down-regulated in CD11b+ macrophages recruited to mouse fibrotic liver and to patient cirrhotic liver regardless of cirrhosis etiology. Prolonged inflammation with TNF-α progressively reduced macrophage RNF41 expression. We designed a macrophage-selective gene therapy with dendrimer-graphite nanoparticles (DGNPs) to explore the influence of macrophage RNF41 restoration and depletion in liver fibrosis and regeneration. RNF41 expression induced in CD11b+ macrophages by DGNP-conjugated plasmids ameliorated liver fibrosis, reduced liver injury, and stimulated hepatic regeneration in fibrotic mice with or without hepatectomy. This therapeutic effect was mainly mediated by the induction of insulin-like growth factor 1. Conversely, depletion of macrophage RNF41 worsened inflammation, fibrosis, hepatic damage, and survival. Our data reveal implications of macrophage RNF41 in the control of hepatic inflammation, fibrosis, and regeneration and provide a rationale for therapeutic strategies in chronic liver disease and potentially other diseases characterized by inflammation and fibrosis.

PPAR-γ Agonist GW1929 Targeted to Macrophages with Dendrimer-Graphene Nanostars Reduces Liver Fibrosis and Inflammation.

Macrophages play essential roles during the progression of chronic liver disease. They actively participate in the response to liver damage and in the balance between fibrogenesis and regression. The activation of the PPARγ nuclear receptor in macrophages has traditionally been associated with an anti-inflammatory phenotype. However, there are no PPARγ agonists with high selectivity for macrophages, and the use of full agonists is generally discouraged due to severe side effects. We designed dendrimer-graphene nanostars linked to a low dose of the GW1929 PPARγ agonist (DGNS-GW) for the selective activation of PPARγ in macrophages in fibrotic livers. DGNS-GW preferentially accumulated in inflammatory macrophages in vitro and attenuated macrophage pro-inflammatory phenotype. The treatment with DGNS-GW in fibrotic mice efficiently activated liver PPARγ signaling and promoted a macrophage switch from pro-inflammatory M1 to anti-inflammatory M2 phenotype. The reduction of hepatic inflammation was associated with a significant reduction in hepatic fibrosis but did not alter liver function or hepatic stellate cell activation. The therapeutic antifibrotic utility of DGNS-GW was attributed to an increased expression of hepatic metalloproteinases that allowed extracellular matrix remodeling. In conclusion, the selective activation of PPARγ in hepatic macrophages with DGNS-GW significantly reduced hepatic inflammation and stimulated extracellular matrix remodeling in experimental liver fibrosis.

Nanoparticles to Target and Treat Macrophages: The Ockham's Concept?

Nanoparticles are nanomaterials with three external nanoscale dimensions and an average size ranging from 1 to 1000 nm. Nanoparticles have gained notoriety in technological advances due to their tunable physical, chemical, and biological characteristics. However, the administration of functionalized nanoparticles to living beings is still challenging due to the rapid detection and blood and tissue clearance by the mononuclear phagocytic system. The major exponent of this system is the macrophage. Regardless the nanomaterial composition, macrophages can detect and incorporate foreign bodies by phagocytosis. Therefore, the simplest explanation is that any injected nanoparticle will be probably taken up by macrophages. This explains, in part, the natural accumulation of most nanoparticles in the spleen, lymph nodes, and liver (the main organs of the mononuclear phagocytic system). For this reason, recent investigations are devoted to design nanoparticles for specific macrophage targeting in diseased tissues. The aim of this review is to describe current strategies for the design of nanoparticles to target macrophages and to modulate their immunological function involved in different diseases with special emphasis on chronic inflammation, tissue regeneration, and cancer.

Single-Walled Carbon Nanohorns as Promising Nanotube-Derived Delivery Systems to Treat Cancer.

Cancer has become one of the most prevalent diseases worldwide, with increasing incidence in recent years. Current pharmacological strategies are not tissue-specific therapies, which hampers their efficacy and results in toxicity in healthy organs. Carbon-based nanomaterials have emerged as promising nanoplatforms for the development of targeted delivery systems to treat diseased cells. Single-walled carbon nanohorns (SWCNH) are graphene-based horn-shaped nanostructure aggregates with a multitude of versatile features to be considered as suitable nanosystems for targeted drug delivery. They can be easily synthetized and functionalized to acquire the desired physicochemical characteristics, and no toxicological effects have been reported in vivo followed by their administration. This review focuses on the use of SWCNH as drug delivery systems for cancer therapy. Their main applications include their capacity to act as anticancer agents, their use as drug delivery systems for chemotherapeutics, photothermal and photodynamic therapy, gene therapy, and immunosensing. The structure, synthesis, and covalent and non-covalent functionalization of these nanoparticles is also discussed. Although SWCNH are in early preclinical research yet, these nanotube-derived nanostructures demonstrate an interesting versatility pointing them out as promising forthcoming drug delivery systems to target and treat cancer cells.