Supramolecular and Macromolecular Matrix Nanocarriers for Drug Delivery in Inflammation-Associated Skin Diseases.

Skin is our biggest organ. It interfaces our body with its environment. It is an efficient barrier to control the loss of water, the regulation of temperature, and infections by skin-resident and environmental pathogens.

An Anti-Inflammatory Poly(PhosphorHydrazone) Dendrimer Capped with AzaBisPhosphonate Groups to Treat Psoriasis.

Dendrimers are nanosized, arborescent macromolecules synthesized in a stepwise fashion with attractive degrees of functionality and structure definition. This is one of the reasons why they are widely used for biomedical applications. Previously, we have shown that a poly(phosphorhydrazone) (PPH) dendrimer capped with anionic azabisphosphonate groups (so-called ABP dendrimer) has immuno-modulatory and anti-inflammatory properties towards human immune cells in vitro.

Biodistribution and Biosafety of a Poly(Phosphorhydrazone) Dendrimer, an Anti-Inflammatory Drug-Candidate.

Dendrimers are nanosized, arborescent polymers of which size and structure are perfectly controlled. This is one reason why they are widely used for biomedical purposes. Previously, we showed that a phosphorus-based dendrimer capped with anionic azabisphosphonate groups (so-called ABP dendrimer) has immuno-modulatory and anti-inflammatory properties towards human immune cells in vitro.

Multivalent nanosystems: targeting monocytes/macrophages.

Among all the cellular partners involved in inflammatory processes, monocytes and macrophages are the master regulators of inflammation. They are found in almost all the tissues and are nearly the only cells capable of performing each step of inflammation. Consequently, they stand as major relevant therapeutic targets to treat inflammatory disorders and diseases.

The ABP Dendrimer, a Drug-Candidate against Inflammatory Diseases That Triggers the Activation of Interleukin-10 Producing Immune Cells.

The ABP dendrimer, which is built on a phosphorus-based scaffold and bears twelve azabisphosphonate groups at its surface, is one of the dendrimers that has been shown to display immuno-modulatory and anti-inflammatory effects towards the human immune system. Its anti-inflammatory properties have been successfully challenged in animal models of inflammatory disorders. In this review, we trace the discovery and the evaluation of the therapeutic effects of the ABP dendrimer in three different animal models of both acute and chronic inflammatory diseases.

Nanoparticle-Based Strategies to Treat Neuro-Inflammation.

Neuro-inflammation is a pivotal physio-pathological feature of brain disorders, including neurodegenerative diseases. As such, it is a relevant therapeutic target against which drugs have to be proposed. Targeting neuro-inflammation implies crossing the Blood-Brain Barrier (BBB) to reach the Central Nervous System (CNS).

Pro-Inflammatory Versus Anti-Inflammatory Effects of Dendrimers: The Two Faces of Immuno-Modulatory Nanoparticles.

Dendrimers are soft matter, hyperbranched, and multivalent nanoparticles whose synthesis theoretically affords monodisperse compounds. They are built from a core on which one or several successive series of branches are engrafted in an arborescent way. At the end of the synthesis, the tunable addition of surface groups gives birth to multivalent nano-objects which are generally intended for a specific use.

Poly(phosphorhydrazone) dendrimers: yin and yang of monocyte activation for human NK cell amplification applied to immunotherapy against multiple myeloma.

Human natural killer (NK) cells play a key role in anti-cancer and anti-viral immunity, but their selective amplification in vitro is extremely tedious to achieve and remains one of the most challenging problems to solve for efficient NK cell-based immuno-therapeutic treatments against malignant diseases. Here we report that, when added to ex vivo culture of peripheral blood mononuclear cells from healthy volunteers or from cancer patients with multiple myeloma, poly (phosphorhydrazone) dendrimers capped with amino-bis(methylene phosphonate) end groups enable the efficient proliferation of NK cells with anti-cancer cytotoxicity in vivo. We also show that the amplification of the NK population relies on the preliminary activation of monocytes in the framework of a multistep cross-talk between monocytes and NK cells before the proliferation thereof.

Interaction studies reveal specific recognition of an anti-inflammatory polyphosphorhydrazone dendrimer by human monocytes.

Dendrimers are nano-materials with perfectly defined structure and size, and multivalency properties that confer substantial advantages for biomedical applications. Previous work has shown that phosphorus-based polyphosphorhydrazone (PPH) dendrimers capped with azabisphosphonate (ABP) end groups have immuno-modulatory and anti-inflammatory properties leading to efficient therapeutic control of inflammatory diseases in animal models. These properties are mainly prompted through activation of monocytes.

The key role of the scaffold on the efficiency of dendrimer nanodrugs.

Dendrimers are well-defined macromolecules whose highly branched structure is reminiscent of many natural structures, such as trees, dendritic cells, neurons or the networks of kidneys and lungs. Nature has privileged such branched structures for increasing the efficiency of exchanges with the external medium; thus, the whole structure is of pivotal importance for these natural networks. On the contrary, it is generally believed that the properties of dendrimers are essentially related to their terminal groups, and that the internal structure plays the minor role of an 'innocent' scaffold.

The PPARα pathway in Vγ9Vδ2 T cell anergy.

Phosphoantigens (PAgs) activate Vγ9Vδ2 T lymphocytes, inducing their potent and rapid response in vitro and in vivo. However, humans and nonhuman primates that receive repeated injections of PAgs progressively lose their Vγ9Vδ2 T cell response to them. To elucidate the molecular mechanisms of this in vivo desensitization, we analyzed the transcriptome of circulating Vγ9Vδ2 T cells from macaques injected with PAg.

Repeated intravenous injections in non-human primates demonstrate preclinical safety of an anti-inflammatory phosphorus-based dendrimer.

Dendrimers are nanosized hyperbranched polymers synthesized through an iterative step-by-step process; their size and structure are perfectly controlled, and they are widely used for biomedical purposes. Previously, we showed that a phosphorous-based dendrimer capped with anionic AzaBisPhosphonate groups (so-called ABP dendrimer) has immunomodulatory and anti-inflammatory properties toward the human immune system. It dramatically inhibits the onset and development of experimental arthritis in a mouse model relevant for human rheumatoid arthritis, a chronic inflammatory disease of auto-immune origin.

Modulation of pro-inflammatory activation of monocytes and dendritic cells by aza-bis-phosphonate dendrimer as an experimental therapeutic agent.

Introduction: Our objective was to assess the capacity of dendrimer aza-bis-phosphonate (ABP) to modulate phenotype of monocytes (Mo) and monocytes derived dendritic cells (MoDC) activated in response to toll-like receptor 4 (TLR4) and interferon γ (IFN- γ) stimulation.

Methods: Mo (n = 12) and MoDC (n = 11) from peripheral blood of healthy donors were prepared. Cells were preincubated or not for 1 hour with dendrimer ABP, then incubated with lipopolysaccharide (LPS; as a TLR4 ligand) and (IFN-γ) for 38 hours.

An azabisphosphonate-capped poly(phosphorhydrazone) dendrimer for the treatment of endotoxin-induced uveitis.

Over the last decade, different types of dendrimers have shown anti-inflammatory properties in their own right. In particular, we have shown that poly(phosphorhydrazone) (PPH) dendrimers are able to foster an efficient anti-inflammatory response in human monocytes and can resolve the main physiopathological features of chronic arthritis in mice at 1 mg/kg. Here we afford new insights into the therapeutic potential of an azabisphosphonate-capped dendrimer (dendrimer ABP).

The gene expression profile of phosphoantigen-specific human γδ T lymphocytes is a blend of αβ T-cell and NK-cell signatures.

Global transcriptional technologies have revolutionised the study of lymphoid cell populations, but human γδ T lymphocytes specific for phosphoantigens remain far less deeply characterised by these methods despite the great therapeutic potential of these cells. Here we analyse the transcriptome of circulating TCRVγ(+) γδ T cells isolated from healthy individuals, and their relation with those from other lymphoid cell subsets. We report that the gene signature of phosphoantigen-specific TCRVγ(+) γδ T cells is a hybrid of those from αβ T and NK cells, with more 'NK-cell' genes than αβ T cells have and more 'T-cell' genes than NK cells.

Anti-inflammatory properties of dendrimers per se.

Dendrimers are polybranched and polyfunctionalized tree-like polymers. Unlike linear polymers, they have perfectly defined structure and molecular weight, due to their iterative step-by-step synthesis. Their multivalent structure and supramolecular properties have made them attractive nanotools for applications, particularly in biology and medicine.

Phosphoantigens overcome human TCRVgamma9+ gammadelta Cell immunosuppression by TGF-beta: relevance for cancer immunotherapy.

Human gammadelta cells expressing TCRVgamma9 are HLA-unrestricted CTLs with high relevance for cancer immunotherapy. Many tumor cell types produce TGF-beta, however, a cytokine strongly immunosuppressive for conventional T CD4, CD8, and NK cells. Whether TGF-beta also inhibits TCRVgamma9+ lymphocytes was unknown.

Anti-inflammatory and immunosuppressive activation of human monocytes by a bioactive dendrimer.

The monocyte-macrophage (MPhi) lineage can undergo different pathways of activation. The classical priming by IFN-gamma, then triggering by LPS, conducts MPhi toward proinflammatory responses, whereas the alternative activation by IL-4, IL-10, IL-13, or glucocorticoids directs them toward an anti-inflammatory, immunosuppressive phenotype. Recently, we have shown that synthetic phosphorus-containing dendrimers activate human monocytes.

Multigenic control of hepatic iron loading in a murine model of hemochromatosis.

Background & Aims: Hereditary hemochromatosis is a common disorder of iron homeostasis characterized by increased dietary iron absorption and progressive iron accumulation, mainly in the liver. Most patients are homozygous for the C282Y mutation in the HFE gene. However, not all individuals carrying the hemochromatosis-predisposing genotype in the general population become iron loaded.

Strain and gender modulate hepatic hepcidin 1 and 2 mRNA expression in mice.

Hepcidin (HEPC) plays a key role in iron homeostasis and an abnormally low level of hepcidin mRNA has been reported in HFE-1 genetic hemochromatosis. Considering the well-known phenotypic variability of this disease, especially between men and women, it is important to define factors susceptible to modulate hepatic hepcidin expression and, consequently, to influence the development of iron overload in HFE-1 hemochromatosis. Therefore, our aim was to analyze the effects of strain and gender on hepatic hepcidin expression in the mouse.

Inactivation of the hemochromatosis gene differentially regulates duodenal expression of iron-related mRNAs between mouse strains.

Background & Aims: Hfe knockout mice, like patients with hereditary hemochromatosis, have augmented duodenal iron absorption and increased iron deposition in hepatic parenchymal cells. The goals of the present study were to gain further insight into the control of iron absorption by comparing the transcript levels of iron-related genes in the duodenum of DBA/2 Hfe-/- mice, susceptible to iron loading, and wild-type controls, and to test whether variations in the duodenal expression of these messengers contribute to the DBA/2 and C57BL/6 strain differences in the severity of hepatic iron loading.

Methods: Expression of the different transcripts was quantified by real-time polymerase chain reaction.