Investigation of structural and thermal properties of solid lipid-based nanocarriers optimized by microfluidic synthesis

In the past decade, lipid-based nanocarriers have gained increasing popularity as the emergent technology for drug delivery, owing to the capability to protect the bioactive cargo and improve intracellular transport and release. Since their approval for clinical usage several lipid nanocarrier formulations were investigated to obtain optimal physicochemical properties and enhanced therapeutic efficacy. Among the factors influencing structure, stability and cellular uptake, the choice of lipid components plays a major role. Moreover, surfactant coatings mediate interactions with membranes and provide stealth and permeation properties. Thus, manipulation of composition and relative abundance results in dramatic modification of physicochemical properties and functionality. Microfluidic-assisted preparation of lipid nanocarriers allows to obtain stable formulations with high reproducibility, boosting screening and optimization potential. However, the fundamental understanding of the mechanism and kinetics of assembly of these systems is still lacking. This knowledge is crucial since early-stage aggregation and transient structures of non-equilibrium systems influence their stability, storage and shelf life, thus impacting greatly on formulation efficacy. In this work, high-throughput screening and optimization of two types of nanocarriers based on solid lipids, i.e. SLNs and NLCs are proposed. Microfluidic synthesis allowed the screening of lipid/surfactant components and instrumental settings following an experimental design approach. By this method, robust models were obtained to describe the influence of each parameter on the final nanocarrier properties. Supramolecular and thermal characterization by means of Dynamic Light Scattering, synchrotron static and Time-Resolved Small Angle X-ray Scattering, Differential Scanning Calorimetry, and quantification of encapsulation efficiency of two model drugs by High Performance Liquid Chromatography gave significant insights for rational design of lipid-based nanoparticles. The fundamental understanding of the mechanism and kinetics of assembly of these systems allowed to correlate structural and dynamic properties to carrier functionality and stability.