Length vs. stiffness: which plays a dominant role in the cellular uptake of fructose-based rod-like micelles by breast cancer cells in 2D and 3D cell culture models?

Polymeric nanoparticles with long circulation time hold great promise for anti-cancer drug delivery. An enhanced circulation effect of rod-like micelles has been reported, yet efficient intracellular delivery, especially their interactions with cells during endocytosis, still remains inconsistent. Internalization of rod-like nanoparticles is significantly affected by a number of factors including aspect ratio, stiffness and surface chemistry of nanoparticles. Our previous research has shown that the length of rods affected their cellular uptake by breast cancer cells. Here, the influence of rod stiffness in cellular uptake was investigated to provide a comprehensive understanding of the interaction between rods and cells during endocytosis. Well-defined fructose-coated rod-like micelles of different lengths and stiffness were prepared successfully. The AFM results indicate that rods based on poly(1-O-MAFru)₃₁-b-PMMA₁₆₆ are significantly stiffer than those prepared from poly(1-O-MAFru)₃₁-b-PBA₁₅₈. The cellular uptake of these different rod-like micelles by breast cancer cells was investigated. In vitro studies via 2D and 3D cell culture models reveal that stiffer rods exhibit a higher cellular uptake and a deeper penetration into cells than the soft rod-like micelles. These results indicate that the internalization of rod-like micelles is significantly affected by their stiffness, though the length of rods also plays an important role. Our results yield a fundamental understanding of the stiffness effect of rod-like micelles on cellular uptake.