Designing nanoparticles with improved tumor penetration: surface properties from the molecular architecture viewpoint.

Cancer is the second most common cause of death, and nanomedicine is regarded as one of the strategies that may revolutionize cancer treatments. However, the tumor microenvironment (e.g., increased interstitial fluid pressure and dense extracellular matrix) hinders the penetration of nanomedicine into tumor cells, which leads to a short acting time and low drug concentration with tumors, eventually leading to a high recurrence rate and therapeutic failure in clinics. Developing a delivery system with deep penetration ability into the tumor has always been pursued and highly desirable for cancer treatments. Inspired by the high cellular uptake efficiency of enveloped viruses with rough and nanoscale surfaces, we constructed polystyrene nanoparticles (NPs) with similar sizes and charges, but with different surface topologies at the molecular level, by conjugating poly(propylene imine) (PPI) dendrimers with different generations onto the NPs. We found that subtle changes made to the surficial chemical properties led to changes in surface roughness and wettability, which considerably influenced the cellular internalization, endocytosis mechanism, and penetration into the tumor model both in vitro and in vivo. This will shed light on the future design of drug delivery vehicles and facilitate understanding the interactions between NP surfaces and cells, as well as tumor penetration.