Mediating bio-fate of polymeric cholecalciferol nanoparticles through rational size control

Whilst 10-200 nm polymeric nanoparticles hold enormous medical potential, successful clinical translation remains scarce. There is an inadequate understanding of how these nanoparticles could be fabricated with consistent particle architecture in this size range, as well as their corresponding biological performance. We seek to fill this important knowledge gap by employing Design of Experiment (DoE) to examine critical formulation and processing parameters of cholecalciferol (VitD3)-loaded nanoparticles by flash nanoprecipitation (FNP). Based on the regression analysis of the critical processing parameters, six VitD3 nanoparticle formulations with z-average particle sizes between 40 and 150 nm were successfully developed, possessing essentially the same particle shape and zeta potential. To evaluate the effect of particle size on the in vivo performance, not only VitD3 but also its active metabolites (25-hydroxyvitamin D3 and 1,25-dihydroxyvitamin D3) were assayed in the biodistribution study. Results indicated that VitD3 nanoparticles with sizes ≤110 nm would achieve higher plasma retention. VitD3 nanoparticles with sizes of 40 nm and 150 nm were superior for lung deposition, while particle size had no major role in the brain uptake of VitD3 nanoparticles. The present study demonstrates the value of DoE for generating size-tunable nanoparticles with controlled particle properties in FNP and offers important insights into the particle size effect of nanoparticles <200 nm on their therapeutic potential.