In-silico investigation into nanoparticle formation, selective active compound delivery into cancer cells and transcytosis across the blood-brain barrier

Targeted delivery of drugs for the treatment of cancer is a major challenge. Current methods of treatment come with adverse side-effects arising from the lack of selectivity and growing resistance to these methods. This results in an urgent medical need to develop and optimise drug delivery vehicles that accumulate only at the target tissue. Using nanoparticles (NPs) to deliver chemotherapeutics has shown improved cellular uptake and selectivity towards cancer cells, reducing off-target effects. However, the mechanistic details of NP formation, drug cargo release, and selective delivery into cancer cells remain poorly understood. Here, we explore the delivery of polymeric NPs, loaded with a potent novel anticancer peptide, with the goal of improving the treatment for gliomas. We employ molecular dynamics (MD) simulations to assess the molecular-level details involved in the selectivity of these NPs for glioma cells in comparison to healthy brain cells, as well as the transcytosis of the NP across human brain microvascular endothelial cells (hBMECs), which comprise the blood-brain barrier (BBB). The simulations allow us to assess which factors contribute to the selectivity of NPs towards gliomas and the mechanisms behind their ability to cross the BBB.