Thermo-responsive lipophilic NIPAM-based block copolymers as stabilizers for lipid-based cubic nanoparticles

The design of drug delivery systems (DDS) for the encapsulation of therapeutic agents and the controlled release to the target site of the disease is one of the main goals of nanomedicine. Although already explored in an extensive number of studies over the years, lipid assemblies, and particularly liposomes, are still considered the most promising and interesting candidates as DDS due to their biocompatibility and structural similarity with plasma membranes. Lately, this research area has been extended to include more complex lipid assemblies, such as cubosomes. Cubosomes are an emerging structural platform for the delivery of molecules with pharmaceutical interest, such as drugs, bioactives and contrast agents. Here we report on the application of a thermo-responsive copolymer poly(N,N-dimethylacrylamide)-block-poly(N-isopropylacrylamide) (PDMA-b-PNIPAM), as a thermoresponsive stabilizer of lipid-based nanoparticles for drug-delivery. First, we assessed the affinity of PDMA-b-PNIPAM towards supported and free-standing bilayers; then, we explored the colloidal and thermoresponsive properties of cubic self-assembled DDS composed of glycerol-monooleate (GMO), where PDMA-b-PNIPAM replaces the conventional stabilizer Pluronic F127 (PEOx-PPOy-PEOx), normally used for cubosomes. We prepared dispersions of cubic lipid nanoparticles with two PDMA-b-PNIPAM block copolymers of different molar mass. The colloidal properties were then assessed and compared to those exhibited by standard lipid cubic dispersions stabilized by Pluronic F-127, combining a series of experimental techniques (Quartz Crystal Microbalance with Dissipation monitoring, Dynamic Light Scattering, Small-Angle X-rays Scattering, Cryo-Transmission Electron Microscopy). Interestingly, PDMA-b-PNIPAM stabilized cubosomes display additional benefits with respect to those stabilized by Pluronic, thanks to the combination of a "sponge " effect for the controlled release of encapsulated molecules and an increased affinity towards lipid bilayer membranes, which is a promising feature to maximize fusion with the target-cellular site.