Abstract
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. Thereafter, we have shown that the ABP dendrimer has a promising therapeutic efficacy to treat models of chronic inflammatory disorders. On the way to clinical translation, the biodistribution and the safety of this drug-candidate has to be thoroughly assessed. In this article, we present preliminary non-clinical data regarding biodistribution, hematological safety, genotoxicity, maximal tolerated doses, and early cardiac safety of the ABP dendrimer. One of the genotoxicity assays reveals a potential mutagen effect of the item at a concentration above 200 µM, i.e., up to 100 times the active dose in vitro on human immune cells. However, as the results obtained for all the other assays show that the ABP dendrimer has promising biodistribution and safety profiles, there is no red flag raised to hamper the regulatory pre-clinical development of the ABP dendrimer.
Highlights
Dendrimers are nanosized non-linear polymers synthesized through a stepwise iterative process.their size and structure are perfectly defined, and their controlled synthesis affords consistent batches of monodisperse compounds
Along repeated intravenous injections in cynomolgus monkeys (Macaca fascicularis), we have shown that the ABP dendrimer has no deleterious effects
In preclinical mouse models chronic inflammatory disorders, we have test proven the therapeutic determine whether there was a significant difference between the observed frequencies of efficacy of the ABP dendrimer through IV injections [8,11]
Summary
Dendrimers are nanosized non-linear polymers synthesized through a stepwise iterative process. Their size and structure are perfectly defined, and their controlled synthesis affords consistent batches of monodisperse compounds. Some of their intrinsic features such as their supramolecular properties, their size and globular shape, and their multivalency make them attractive nanomolecules. Dendrimers can be divergently built on a central core on which a first series of radial branches ending by a point of divergence is linked. The latter enables the dendritic growth of the molecule by addition of supplemental branches, if any. We have shown that a first generation (G1) phosphorus-based dendrimer capped with anionic azabisphosphonate groups (so-called ABP dendrimer, Figure 1A)
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