Role of Endocytosis in Nanoparticle Penetration of 3D Pancreatic Cancer Spheroids.

Robust deposition of extracellular matrix is a significant barrier for delivery of nanotherapeutics and small-molecule anticancer drugs to different tumors including pancreatic ductal adenocarcinoma. Here, we investigated permeation and total uptake of polystyrene nanoparticles of different diameters in 3D multicellular spheroid models of pancreatic tumors. Special attention was given to analysis of the impact of endocytic processes on nanoparticle accumulation and distribution in spheroids. We generated spheroids of BxPC3 or PANC-1 cells that were able to internalize 20, 100, and 500 nm fluorescent polystyrene beads with different efficacies, resulting in 20 ≫100 > 500 nm and 100 > 500 > 20 nm trends, respectively. It was found that endocytosis and transcytosis increased overall nanoparticle uptake and facilitated permeation of 20 nm beads in BxPC3 spheroids, whereas 100 and 500 nm particles did not penetrate. In PANC-1 spheroids, penetration of nanoparticles also decreased with the increase of size but was not significantly affected by endocytic processes. Thus, our study showed that passive diffusion and endocytic processes may have a different contribution to nanoparticle accumulation and distribution in spheroid models of pancreatic cancer.