Cédric-Olivier Turrin

A Phosphorus-Based Dendrimer Targets Inflammation and Osteoclastogenesis in Experimental Arthritis

A phosphorus-based dendrimer suppresses inflammation and reduces bone erosion in mouse models of rheumatoid arthritis. Dendrimer Doubles Up Rheumatoid arthritis (RA) is an autoimmune inflammatory disease that is characterized by inflamed synovial tissue, cartilage degeneration, and bone erosion, leading to joint deformation and physical handicap. Biologic therapeutic approaches, such as monoclonal antibodies and soluble receptors, have been developed to relieve the symptoms of RA. Unfortunately, these drugs typically act on a single target: proinflammatory cytokines. There is an unmet clinical need for anti-RA drugs that target not only proinflammatory molecules and pathways, but also the osteoclastic differentiation of monocytes—a process that leads to bone resorption. In response, Hayder et al. synthesized a new dendrimer-based therapeutic that boasts a two-pronged attack on RA, with both anti-inflammatory and anti-osteoclastogenic activity. Dendrimers are highly branched polymers whose multivalency allows for interaction with several cellular and molecular targets. The authors created an azabisphosphonate (ABP)–capped dendrimer that has been shown to target human monocytes and direct them toward an anti-inflammatory response. Two animal models of autoimmune arthritis were used: the IL-1ra−/− mouse and the K/BxN serum transfer mouse. Dendrimer ABP was administered to IL-1ra−/− mice via weekly intravenous injections. At high doses, the dendrimer completely inhibited inflammation, as evidenced by a decrease in paw swelling, and prevented arthritis histopathology, with ankle joints showing near-normal synovial membranes and intact cartilage after 12 weeks. Dendrimer ABP also decreased the amount of proinflammatory cytokines and increased levels of anti-inflammatory cytokines interleukin-4 (IL-4) and IL-10, thereby suggesting a skewing toward a T helper 2 (TH2) response. The K/BxN mouse demonstrated similar results upon treatment with dendrimer ABP. Treatment with dendrimer ABP also prevented osteoclastogenesis, as shown in human synovial tissue ex vivo and human peripheral blood monocytes in vitro. The authors further outlined a potential dendrimer-mediated mechanism that involves inhibition of c-FMS—a signaling molecule that promotes monocyte differentiation into osteoclasts. This study by Hayder and colleagues has shown that dendrimer ABP, by doubling up against inflammation and bone erosion, might be more effective at treating RA than existing antibody- and small-molecule–based biologic drugs. Dendrimers are highly branched “tree-like” polymers that have demonstrated therapeutic potential in drug delivery, medical imaging, and tissue engineering in recent years. In addition, we have shown that an azabisphosphonate (ABP)–capped dendrimer selectively targets monocytes and directs them toward anti-inflammatory activation. We explored this property to assess the therapeutic potential of dendrimer ABP in the treatment of an inflammatory disease, rheumatoid arthritis. Intravenous injections of dendrimer ABP inhibited the development of inflammatory arthritis in two animal models: IL-1ra−/− mice and mice undergoing K/BxN serum transfer. Suppression of disease was characterized by normal synovial membranes, reduced levels of inflammatory cytokines, and the absence of cartilage destruction and bone erosion. Dendrimer ABP also exhibited anti-osteoclastic activity on mouse and human cells, mediated by c-FMS (cellular-feline McDonough strain sarcoma virus oncogene homolog) inhibition. These preclinical demonstrations suggest the potential use of dendrimer ABP as a nanotherapeutic for rheumatoid arthritis.

Designing dendrimers for ocular drug delivery

New series of phosphorus-containing dendrimers, having one quaternary ammonium salt as core and carboxylic acid terminal groups have been synthesized from generation 0 (3 carboxylic acid terminal groups) to generation 2 (12 carboxylic acid terminal groups). These dendrimers react with the neutral form of carteolol (an ocular anti-hypertensive drug used to treat glaucoma) to afford ion pair (saline) species. The solubility in water of these charged dendrimers depends on the generation considered: generation 0 (3 carteolol) is well soluble, whereas generation 1 (6 carteolol) and generation 2 (12 carteolol) are poorly soluble. These dendrimers have been tested in vivo, as vehicle for ocular drug delivery of carteolol to rabbits.

Dendrimers and DNA : Combinations of Two Special Topologies for Nanomaterials and Biology

Interactions between two precisely defined three-dimensional architectures (DNA and dendrimers) are described. Highly synergetic effects occur, as illustrated in two cases: dendrimers can be used as three-dimensional linkers for oligonucleotides, affording highly sensitive microarrays (biochips), and positively charged dendrimers strongly interact with DNA, allowing penetration inside cells (genetic transfection).

Dendrimers : towards catalytic, material and biomedical uses

This book will be mainly focussed on the properties and uses of dendrimers and dendrons. The aim of this book is to be the reference book about dendrimers applications. It will not describe all details, but it will give the reader a unique overview of what has currently been done with dendrimers, with numerous references and illustrations. It will be divided in four main parts: Part 1) Generalities, syntheses, characterizations and properties; Part 2) Applications in catalysis; Part 3) Applications for the elaboration or modification of materials; and Part 4) Applications in biology/medicine. The role of the nanometric size and the multiple functions of dendrimers on the properties will be emphasized.

Tailored Control and Optimisation of the Number of Phosphonic Acid Termini on Phosphorus‐Containing Dendrimers for the Ex‐Vivo Activation of Human Monocytes

The syntheses of a series of phosphonic acid-capped dendrimers is described. This collection is based on a unique set of dendritic structural parameters-cyclo(triphosphazene) core, benzylhydrazone branches and phosphonic acid surface-and was designed to study the influence of phosphonate (phosphonic acid) surface loading towards the activation of human monocytes ex vivo. Starting from the versatile hexachloro-cyclo(triphosphazene) N(3)P(3)Cl(6), six first-generation dendrimers were obtained, bearing one to six full branches, that lead to 4, 8, 12, 16, 20 and 24 phosphonate termini, respectively. The surface loading was also explored at the limit of dense packing by means of a first-generation dendrimer having a cyclo(tetraphosphazene) core and bearing 32 termini, and with a first-generation dendrimer based on a AB(2)/CD(5) growing pattern and bearing 60 termini. Human monocyte activation by these dendrimers confirms the requirement of the whole dendritic structure for bioactivity and identifies the dendrimer bearing four branches, thus 16 phosphonate termini, as the most bioactive.

Dendrimers for drug delivery

Due to their nanometric size, dendrimers have been considered as potentially suitable as new vehicles for drug delivery since their infancy. The association of a dendrimer and a drug may occur in different ways, either through covalent or non-covalent interactions. A non-covalent interaction can be the simple encapsulation inside dendrimers that enhances the solubility of lipophilic drugs in water, or electrostatic interactions between the surface and charged drugs (or DNA, RNA, or siRNA). The covalent association may occur through stable bonds, in particular for dendrimers that are considered as active per se, or through cleavable bonds that should be cleaved only when reaching the target (often cancerous cells). In addition, the full structure of the dendrimer can be disassembled under the influence of a trigger such as pH variations. This review will present these strategies and their consequences for drug delivery.

Biological properties of phosphorus dendrimers

This review will display the special role played by phosphorus-containing dendrimers when interacting with biological systems. After some synthetic aspects, the usefulness of these dendrimers for elaboration of highly sensitive bio-sensors and for in vitro drug delivery (for instance as transfection agents, or against HIV-1 and the scrapie form of prions) will be demonstrated. Then, emphasis will be put on the favourable influence of these dendrimers on cells growth, in particular for neuronal cells, and for human immune blood cells such as monocytes and Natural Killer cells, the latter playing a key-role for fighting against viral infections and cancers. This review will finally describe in vivo biological properties of these phosphorus dendrimers as anti-prion agents, for ocular drug delivery, and for imaging rat brain blood vessels. Some of these properties can be found also with other types of dendrimers, but others, in particular the interaction with the human immune blood cells, occur only and specifically with phosphorus dendrimers.

Dendritic Catanionic Assemblies: In vitro Anti‐HIV Activity of Phosphorus‐Containing Dendrimers Bearing Galβ1cer Analogues

Two series of water‐soluble dendritic catanionic assemblies, acting as multisite analogues of galactosylceramide (Galβ1cer), have been prepared with the goal of blocking HIV infection prior to the entry of the virus into human cells. Trifunctional and hexafunctional cinnamic acid‐terminated dendrimers have been synthesized from phosphorus‐containing dendrimers bearing aldehyde end groups. A classical acid–base reaction performed in water between acid‐terminated dendrimers and stoichiometric amounts of N‐hexadecylamino‐1‐deoxylactitol (3) provided the expected catanionic assemblies. Antiviral assays on these supramolecular entities confirmed the crucial roles both of multivalency effects and of lipophilicity on the biological activity of Galβ1cer analogues. Moreover, correlation between in vitro tests and molecular modeling highlights the specific influence of the assembly shape on the anti‐HIV efficiency, with the tri‐ and hexafunctional cored dendrimers, both decorated with 12 sugar moieties, exhibiting IC50 values of 1.1 and 0.12 μM, respectively.

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

The monocyte‐macrophage (MΦ) lineage can undergo different pathways of activation. The classical priming by IFN‐γ, then triggering by LPS, conducts MΦ 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. Here, we analyzed the gene expression of monocytes activated by an acid azabisphosphonic‐capped, phosphorus‐containing dendrimer by comparison with untreated monocytes. We found that 78 genes were up‐regulated, whereas 62 genes were down‐regulated. Analysis of these genes directed the hypothesis of an alternative‐like, anti‐inflammatory activation of human monocytes. This was confirmed by quantitative RT‐PCR and analysis of the surface expression of specific markers by flow cytometry. Functional experiments of inhibition of CD4+ T‐lymphocyte proliferation in MLR indicated that dendrimer‐activated monocytes (da‐monocytes) have an immune‐suppressive phenotype similar to the one induced by IL‐4. Moreover, da‐monocytes preferentially enhanced amplification of CD4+ T cells, producing IL‐10, an immunosuppressive cytokine. Therefore, phosphorus‐containing dendrimers appear as new nanobiotools promoting an anti‐inflammatory and immunosuppressive activation of human monocytes and thus, prove to be good candidates for innovative, anti‐inflammatory immunotherapies.

Naked Au55 Clusters: Dramatic Effect of a Thiol‐Terminated Dendrimer

Reaction of the thiol-terminated fourth-generation dendrimer 2-G4 (96 SH groups) with the gold cluster compound Au55(PPh3)12Cl6 in a 3:1 molar ratio in dichloromethane results in the formation of bare Au55 clusters. The cuboctahedrally shaped Au55 particles coalesce to well-formed microcrystals (Au55) infinity. The role of the dendrimer is not only to remove the phosphine and chlorine ligands but also to act as an ideal matrix for perfect crystal growth. Transmission electron microscopy (TEM), small- and wide-angle X-ray diffraction (SAXRD and WAXRD) measurements indicate a structure where rows of edge-linked Au55 building blocks form a distorted cubic lattice. The X-ray data fit best if a 5% reduction of the Au-Au bond length in the Au55 clusters is assumed, in agreement with previous extended X-ray absorption fine structure (EXAFS) measurements. Energy-dispersive X-ray spectroscopy (EDX) analyses and IR investigations show the absence of PPh3 and Cl in the microcrystals.