The Trigeminal Pathway Dominates the Nose-to-Brain Transportation of Intact Polymeric Nanoparticles: Evidence from Aggregation-Caused Quenching Probes

Nasal drug delivery is a fascinating approach to bypass the blood-brain barrier, which instead directly transports drug molecules to the brain from the nasal cavity along the olfactory and trigeminal nerves. However, the feasibility of nose-to-brain transportation of intact nanoparticles and the possible corresponding pathways remain poorly understood. The purpose of the present study is to explore the intranasal fate of curcumin (Cur)-loaded polycaprolactone nanoparticles (PCL NPs) via fluorescent bioimaging strategies. The behavior of intact nanoparticles was tracked by aggregation-caused quenching (ACQ) probes, which provide on-to-off fluorescent switching from loaded to released states. Evidence for the translocation of intact nanoparticles and Cur was collected either via live imaging or ex vivo histological examination in rats after nasal administration. Intact PCL NPs, irrespective of whether or not they are PEGylated, cannot enter into the olfactory bulb from the nasal cavity, whereas free Cur molecules that are released from the nanoparticles can diffuse into the olfactory bulb. Both PCL NPs and PEGylated PCL NPs carrying Cur can permeate into the mucosa and the trigeminal nerves. Although PEGylation improves the nasal retention of NPs and mucus-penetration, it reduces permeation of NPs into the trigeminal nerves. Transportation of NPs along the trigeminal nerves is slow. Neither the carriers nor the Cur signals are found in the brain at 1 h post-administration. However, starting at 2 h post-administration, both intact nanoparticles and Cur are transported into the brainstem, as exemplified by the presence of Cur-loaded PEGylated PCL NPs. Nanoparticles reaching the brainstem can further distribute to other parts of the brain such as the middle brain. We conclude that the trigeminal nerve pathway, instead of the olfactory nerve route, dominates the nose-to-brain delivery of intact polymeric nanoparticles.