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An amphiphilic prodrug of gemcitabine, a cytidine analogue used clinically against various tumors, had been previously synthesized by covalent coupling to squalene, a natural isoprenoid chain. The resulting bioconjugate self-assembled spontaneously in water as nanoparticles, displaying an impressive activity both in vitro and in vivo. The aim of the present study was to determine the influence of the length of the isoprene moiety on the structure of the nanoparticles, in an attempt to establish a relationship between the chemical structure of the prodrug, its supramolecular organization, and its pharmacological activity. Remarkably, gemcitabine-squalene and gemcitabine-5-isoprenes, which differ only in the position of two methyl groups on the hydrophobic chain, displayed different supramolecular organizations and different anticancer activities on some cell lines. This difference in activity was related to the ability of nanoparticles to be internalized by cells.

Squalene-based nucleolipids, including anticancer or antiviral prodrugs, gave rise to nanoparticles displaying a diversity of structures upon nanoprecipitation in water. Synchrotron small-angle X-ray scattering and cryo-TEM imaging revealed that both the nature of the nucleoside and the position of the squalene moiety relative to the nucleobase determined the self-assembly of the corresponding bioconjugates. It was found that small chemical differences resulted in major differences in the self-organization of nucleolipids when squalene was grafted onto the nucleobase whereas only lamellar phases were observed when squalene was linked to the sugar moiety. The key role of hydrogen bonds between nucleobases in the formation of the lamellar phases was suggested, in agreement with molecular simulations. These findings provide a way to fine tune the supramolecular organization of squalene-based prodrugs, with the aim of improving their pharmacological activity.

We study the influence of nanoparticle doping on the lyotropic liquid crystalline phase of the industrial surfactant Brij®30 (C₁₂E₄) and water, doped with spherical polyoxometalate nanoparticles smaller than the characteristic dimensions of the host lamellar phase. We present viscometry and in situ rheology coupled with small-angle X-ray scattering data that show that, with increasing doping concentration, the nanoparticles act to decrease the shear viscosity of the lamellar phase, and that a shear-induced transition to a multilamellar vesicle "onion" phase is pushed to higher shear rates, and in some cases completely suppressed. X-ray data reveal that the nanoparticles remain encapsulated within the membranes of the vesicles, thus indicating a viable method for the fabrication of nanoparticle incorporating organic vesicles.