Pascal Clayette

Nucleoside analogues display significant anticancer or antiviral activity by interfering with DNA synthesis. However, there are some serious restrictions to their use, including their rapid metabolism and the induction of resistance. We have discovered that the linkage of nucleoside analogues to squalene leads to amphiphilic molecules that self-organize in water as nanoassemblies of 100-300 nm, irrespective of the nucleoside analogue used. The squalenoyl gemcitabine exhibited superior anticancer activity in vitro in human cancer cells and gemcitabine-resistant murine leukemia cells, and in vivo in experimental leukemia both after intravenous and oral administration. The squalenoylation of other antiretroviral nucleosides also led to more potent drugs when tested in primary cultures of HIV-infected lymphocytes. Thus, the squalenoylation is an original technology platform for generating more potent anticancer and antiviral nanomedicines.

Nanoscale mesoporous iron carboxylates metal-organic frameworks (nanoMOFs) have recently emerged as promising platforms for drug delivery, showing biodegradability, biocompatibility and important loading capability of challenging highly water-soluble drugs such as azidothymidine tryphosphate (AZT-TP). In this study, nanoMOFs made of iron trimesate (MIL-100) were able to act as efficient molecular sponges, quickly adsorbing up to 24 wt% AZT-TP with entrapment efficiencies close to 100%, without perturbation of the supramolecular crystalline organization. These data are in agreement with molecular modelling predictions, indicating maximal loadings of 33 wt% and preferential location of the drug in the large cages. Spectrophotometry, isothermal titration calorimetry, and solid state NMR investigations enable to gain insight on the mechanism of interaction of AZT and AZT-TP with the nanoMOFs, pointing out the crucial role of phosphates strongly coordinating with the unsaturated iron(III) sites. Finally, contrarily to the free AZT-TP, the loaded nanoparticles efficiently penetrate and release their cargo of active triphosphorylated AZT inside major HIV target cells, efficiently protecting against HIV infection.