Matrix Stiffness Differentially Regulates Cellular Uptake Behavior of Nanoparticles in Two Breast Cancer Cell Lines

Matrix stiffness regulates cell behavior in various biological contexts. In breast tumors, the deposition of extracellular matrix correlates with increasing matrix stiffness and poor survival. Nanoparticulate carriers represent a promising therapeutic vehicle for disease diagnosis and efficient anticancer drug delivery. However, how matrix stiffness influences cellular uptake of nanoparticles remains largely unexplored. Here, we selected photopolymerized polyacrylamide gels with varying stiffnesses as model substrates and studied the impact of matrix stiffness on cell morphology and nanoparticle uptake efficiency in two representative breast cancer cell lines with varying invasiveness, that is, MCF-7 with low invasiveness and MDA-MB-231 with high invasiveness. In our study, both cell lines showed similar morphological changes with changing stiffness. MCF-7 cells adhered on compliant substrates (1 kPa) showed a roundlike morphology with the lowest cell uptake efficiency among four stiffnesses under investigation at each given time point, whereas for MDA-MB-231 cells, the uptake efficiency showed no significant differences across varying stiffnesses. The percentages of MCF-7 cell proliferation on a 1 kPa substrate were significantly decreased at 48 and 72 h as compared to those on stiff substrates and coverslips. When treated with pluronic/d-α-tocopheryl polyethylene glycol 1000 succinate mixed micelle-loaded paclitaxel, cells on stiff substrates of 7, 20, and 25 kPa showed higher cell apoptosis rates as compared to those of cells on 1 kPa substrates. To sum up, our work presents an example of how physical cues impact specific cellular behavior and function, which may further contribute to engineering nanoparticulate delivery systems for more efficient delivery in vivo.