Decoupling the Role of Nanoparticle Rigidity and Chemistry in Particle Transport through the Brain Parenchyma

Drug delivery to the brain involves challenging transportation across multiple biological barriers. Despite the great tunability of polymeric nanoparticles, the synthetic challenge of varying the physical property of a nanoparticle without varying its chemical formulation only adds to our limited understanding of this transport. Here, we introduce a method for tuning the rigidity of poly(lactic-co-glycolic acid) (PLGA) nanoparticles without altering the chemical formulation by using UV irradiation to control the crosslinking chemistry. Using atomic force microscopy (AFM), we were able to show that Young's modulus of nanoparticles increased with UV exposure time. Crosslinked nanoparticles with greater rigidity were found to have greater diffusive ability through the brain parenchyma than their non-crosslinked counterparts. However, even with identical chemical formulations, minor differences in the chemical structure of crosslinked and non-crosslinked particles were found to influence transport, highlighting the importance of decoupling the physical properties of nanoparticles from their chemistry.