Aurélien Hameau

Validation of a Generation 4 Phosphorus-Containing Polycationic Dendrimer for Gene Delivery Against HIV-1

Gene therapy, in which oligomeric genetic material is carried into cells by nano-sized gene delivery vehicles to interfere with gene expression, represents a promising approach for preventive therapy against HIV/AIDS pandemic. Herein, we evaluate the usefulness of a phosphorus-containing dendrimer G4(NH+Et2Cl-)96 as a delivery agent of ODNs and siRNAs. G4(NH+Et2Cl-)96 formed stable complexes with ODNs or siRNAs and exhibited very low cytotoxicity in Sup T1 cells or PBMC. Functional validation was performed by using specific siRNA against HIV-1 Nef, siNEF to interfere in HIV-1 replication. G4(NH+Et2Cl-)96/siNEF dendriplex showed a high efficiency in Nef silencing. Furthermore, in vitro treatment of HIV-infected PBMC with G4(NH+Et2Cl-)96/siNEF dendriplex significantly reduced the viral replication. Our results prove the usefulness of phosphorus-containing dendrimers to deliver and transfect siRNA into CD4-T cells as a potential alternative therapy in the HIV-1 infection.

An efficient and recyclable dendritic catalyst able to dramatically decrease palladium leaching in Suzuki couplings

A series of novel monomeric and dendritic thiazolyl phosphines (generations 1 and 3) was prepared and the activity these ligands conferred to palladium in Suzuki couplings was evaluated. The heteroaryl ligands were revealed to be very efficient and were able to perform the reactions in mild conditions. Besides, their efficiency was compared to that of the corresponding triphenylphosphines. Moreover, the possibility to reuse both families of dendritic ligands was explored and the thiazolyl phosphine-based catalytic systems could be successfully recycled for five consecutive reactions without loss of activity, contrary to their triphenylphosphine counterparts. Remarkably, the palladium leaching was found to be dramatically reduced by using the dendrimer-supported thiazolylphosphines instead of the monomeric ligand and only trace amounts of metal (<0.55 ppm) could be found in the coupling product before any purification.

Synthesis of dye/fluorescent functionalized dendrons based on cyclotriphosphazene

Summary Functionalized phenols based on tyramine were synthesized in order to be selectively grafted on to hexachlorocyclotriphosphazene, affording a variety of functionalized dendrons of type AB5. The B functions comprised fluorescent groups (dansyl) or dyes (dabsyl), whereas the A function was provided by either an aldehyde or an amine. The characterization of these dendrons is reported. An unexpected behaviour of a fluorescent and water-soluble dendron based on dansyl groups in mixtures of dioxane/water was observed.

HIV-Antigens Charged on Phosphorus Dendrimers as Tools for Tolerogenic Dendritic Cells-Based Immunotherapy

AIMS The objective was to study if cationic phosphorus dendrimers can be used as DC-based vaccine or adjuvant in anti-HIV-1 vaccine development when associated with HIV-1 derived peptides. MATERIALS & METHODS The HIV derived peptides uptake in DC and the phenotype of iDC and mDC were studied using Flow Cytometry analysis. Migration of mDC was evaluated by an in vitro chemotaxis assay. Allogenic T-cells proliferative response induced by DC was studied using Flow Cytometry assays. Cytokines production was analysed by Diaclon DIAplex Th1/Th2/Inflammation kit. RESULTS All phosphorus dendrimers showed the ability to deliver HIV-derived peptides in DC. The phosphorus dendrimers from second and third generations induced important changes in phenotype. Moreover, the treatment of mDC with the second generation dendrimer and derivated dendriplexes modified cellular migratory properties, altered their capacity to stimulate allogenic naïve T cells in vitro and impeded the production of pro-inflammatory cytokines. CONCLUSIONS The phosphorus dendrimers cannot be used as vaccines because they would not have the ability to induce an immune response. The cationic phosphorus dendrimers associated with HIV-derived peptides have the ability to deliver peptides as non-viral vectors. However, there are other potential therapeutic applications of these compounds, for instance as topical antiinflammatory agents, as compounds for allograft rejection or autoimmune diseases and as agents inducing specific tolerance with antigen-loaded DC against allergy reaction. Nevertheless, these applications need to be evaluated.

PPH dendrimers grafted on silica nanoparticles: surface chemistry, characterization, silver colloids hosting and antibacterial activity

Polyphosphorhydrazone (PPH) dendrimers have been grafted on silica nanoparticles, and the surface functions of the dendrimers have been derivatized to phosphonates with lateral poly(ethyleneglycol) (PEG) chains. All materials have been thoroughly characterized by MAS NMR, FT-IR, electron microscopy, TGA and elemental analysis. These materials successfully hosted silver and silver oxide nanoparticles. The resulting composites exhibit antibacterial activity.

Fluorescent Phosphorus Dendrimers and Their Role in Supramolecular Interactions

Abstract Several types of phosphorus-containing dendrimers bearing fluorescent derivatives in their structures are reviewed. The fluorescent groups can be used as terminal groups, or at the core, or linked to the core or to the branches of the dendritic structure. The types of fluorescent entities used are pyrene, dansyl, phthalocyanine, maleimide, julolidine, rhodamine, and fluoresceine derivatives. Some of these compounds possess interesting properties as chemical sensors, and for monitoring their penetration inside human cells.

Cyclotriphosphazene, an old compound applied to the synthesis of smart dendrimers with tailored properties

Abstract The versatile reactivity of hexachlorocyclotriphosphazene (N3P3Cl6) has been developed for the synthesis of specifically engineered dendrimers. Dendrimers are hyperbranched macromolecules built by concentric layers constituted of associated monomeric units. Many of the properties of dendrimers depend on the type of their surface (terminal) functions, which are generally all identical. For some specific purposes, it is desirable to have one function that is different at the level of the core. Hexachlorocyclotriphosphazene offers the possibility to differentiate the reactivity of one (or more) Cl from the others, for producing specifically engineered dendritic tools. These specific reactions on N3P3Cl6 have produced highly dense dendrimers, Janus dendrimers (two faces), tools for functionalizing materials, with uses as catalysts, as chemical sensors, for trapping CO2, for the culture of cells, or for imaging biological events. These properties will be emphasized in this review.

Synthesis and characterization of dendritic structures incorporating phosphorus, sulfur, and silicon

GRAPHICAL ABSTRACT ABSTRACT Two new families of small phosphorus-containing dendrons, having as core either a phenol protected by a t-butyldimethylsilyl group or a terminal alkyne protected by a trimethylsilyl group have been synthesized. Both families comprise P, S, and Si (and other elements) in their structure. The structure of one of the smallest dendron, having a P(S)Cl2 terminal group, has been determined by X-ray crystallography, showing an almost planar arrangement of a large part of the structure. The P(S)Cl2 terminal group is particularly suitable for further functionalization, as illustrated by the grafting of amines, aldehydes, and dansyl derivatives. These functions were grafted thanks to the reactivity of amines and phenols in basic conditions, demonstrating the compatibility of these reactions with the presence of the protecting groups. Deprotection attempts proved to be difficult, in particular for the purification of the deprotected products. All compounds have been characterized at least by 1H, 13C, and 31P NMR.