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.

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.

What is the contribution of dendrimers to the field of nanomedicine? Rather than disclosing an exhaustive catalogue of their possible applications, this review article sets a putative answer by showing the basics and the underlying concepts that make dendrimeric systems so attractive to nanomedicine, emphasizing on the extraordinary possibilities offered by their multivalent and defined structure.

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.