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.
Schematized types of interactions of dendrimers with drugs or biologically active substances.
As first defensive line, monocytes are a pivotal cell population of innate immunity. Monocyte activation can be relevant to a range of immune conditions and responses. Here we present new insights into the activation of monocytes by a series of phosphonic acid-terminated, phosphorus-containing dendrimers. Various dendritic or subdendritic structures were synthesized and tested, revealing the basic structural requirements for monocyte activation. We showed that multivalent character and phosphonic acid capping of dendrimers are crucial for monocyte targeting and activation. Confocal videomicroscopy showed that a fluorescein-tagged dendrimer binds to isolated monocytes and gets internalized within a few seconds. We also found that dendrimers follow the phagolysosomial route during internalization by monocytes. Finally, we performed fluorescence resonance energy transfer (FRET) experiments between a specifically designed fluorescent dendrimer and phycoerythrin-coupled antibodies. We showed that the typical innate Toll-like receptor (TLR)-2 is clearly involved, but not alone, in the sensing of dendrimers by monocytes. In conclusion, phosphorus-containing dendrimers appear as precisely tunable nanobiotools able to target and activate human innate immunity and thus prove to be good candidates to develop new drugs for immunotherapies.
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. Here we show that such an assertion is misleading, using convergent information from biological data (human monocytes activation) and all-atom molecular dynamics simulations on seven families of dendrimers (13 compounds) that we have synthesized, possessing identical terminal groups, but different internal structures. This work demonstrates that the scaffold of nanodrugs strongly influences their properties, somewhat reminiscent of the backbone of proteins.
Mycobacterium tuberculosis mannose-capped lipoarabinomannan inhibits the release of proinflammatory cytokines by LPS-stimulated human dendritic cells (DCs) via targeting the C-type lectin receptor DC-specific intercellular adhesion molecule 3-grabbing nonintegrin (DC-SIGN). With the aim of mimicking the bioactive supramolecular structure of mannose-capped lipoarabinomannan, we designed and synthesized a set of poly(phosphorhydrazone) dendrimers grafted with mannose units, called mannodendrimers, that differed by size and the number and length of their (α1→2)-oligommanoside caps. A third-generation dendrimer bearing 48 trimannoside caps (3T) and a fourth-generation dendrimer bearing 96 dimannosides (4D) displayed the highest binding avidity for DC-SIGN. Moreover, these dendrimers inhibited proinflammatory cytokines, including TNF-α, production by LPS-stimulated DCs in a DC-SIGN-dependent fashion. Finally, in a model of acute lung inflammation in which mice were exposed to aerosolized LPS, per os administration of 3T mannodendrimer was found to significantly reduce neutrophil influx via targeting the DC-SIGN murine homolog SIGN-related 1. The 3T mannodendrimer therefore represents an innovative fully synthetic compound for the treatment of lung inflammatory diseases. T o secure their colonization and survival, some bacterial intracellular pathogens have evolved tactics to undermine host innate immune responses, including inflammation. Mycobacterium tuberculosis, the causative agent of human tuberculosis, uses multiple mechanisms to survive within its host cellular niches of alveolar macrophages and dendritic cells (DCs). In particular, M. tuberculosis exposes surface lipoglycans at its cell envelope, namely mannose-capped lipoarabinomannans (ManLAMs), which inhibit the production of proinflammatory cytokines IL-12 and TNF-α by LPS-stimulated human DCs (1-3) via binding to the C-type lectin DC-specific intercellular adhesion molecule 3 (ICAM-3)-grabbing nonintegrin (DC-SIGN) (4, 5). DC-SIGN reportedly modulates immune responses to several other pathogens, supporting its important role as an immunomodulatory receptor (6). ManLAMs are complex amphipathic macromolecules with an average molecular weight of 17 kDa that are composed of three domains: (i) a mannosyl-phosphatidyl-myo-inositol (MPI) anchor; (ii) a heteropolysaccharidic core composed of D-mannan and D-arabinan; and (iii) mannose caps consisting of mono, (α1→2)-di-, and (α1→2)-trimannosides (7). MPI anchor fatty acyl appendages induce a supramolecular organization of ManLAMs in aqueous solution, resulting in the formation of a 30-nm spherical structure of ∼450 molecules with the mannose caps exposed at the surface (8). This multivalent supramolecular structure allows multipoint attachment of ManLAMs, via mannose caps, to multimeric DC-SIGN receptors (9, 10) expressed at the surface of DCs, thereby ensuring high-affinity binding to the receptor (8-10) and induction of antiinflammatory activity (1, 2, 7).The strategy used by M. tuberculosis to down-regulate the...
Low-polydispersity copper nanoparticles (NPs) are prepared through hydrogenolysis of various organometallic copper precursors in an organic medium at moderate temperature. The effects of the precursor composition and the nature of the additional surfactants on the structure and stability of NPs are characterized by TEM and UV-Vis analysis. The improved air stability of copper NPs originating from amidinate copper and stabilized by an alkylamine compound (hexadecylamine) is evidenced and compared with the effect of a long chain carboxylic acid (oleic acid).
Non‐natural born killers: The addition of phosphorus‐containing dendrimers capped with phosphonate end groups to cultures of human peripheral blood mononuclear cells (white blood cells) strongly stimulates the selective multiplication of functional natural killer (NK) cells (see picture), which play a key role in anticancer immunity. Both the generation of the dendrimer and the type of end groups are important criteria for the activity.
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