Biomimeting ultra-small lipid nanoconstructs for glioblastoma treatment: A computationally guided experimental approach.

Ultra-small nanostructured lipid carriers (usNLCs) are stable, biocompatible and biodegradable colloidal systems, claiming a broad set of advanced features suitable for cancer drug delivery. To unleash their potential in glioblastoma research and therapy, we have developed an usNLC prototype able to co-encapsulate atorvastatin calcium and curcumin, as repurposed drugs previously screened from molecular dynamics simulations. The novelty not only relies on the drug repositioning approach, but also on a robust computational methodology utilized for formulation optimization, under the umbrella of multivariate analysis and full factorial designs. A coating procedure with red blood cell membranes is ultimately hypothesized, aiming at integrating the biomimetic concept into usNLCs for glioblastoma therapeutics. The formulation composition and process parameters, that demonstrated a high-risk level for the final quality and performance of the usNLCs, include the solid:liquid lipid ratio, type and concentration of liquid lipids and surfactants, along with the type of production method. Particles with an average diameter of ca. 50 nm, and a polydispersity index lower than 0.3 were produced, exhibiting high stability, up-scalability, drug protection and sustained co-release properties, meeting the suitable critical quality attributes for intravenous administration. Also, a Taguchi design was successfully applied to optimizing usNLCs as cell membrane-coating technology.