Comment on “Distribution of Nanoparticles in the See-through Medaka (Oryzias latipes)”

In the study published by Kashiwada (2006), the author investigated the distribution of water-suspended fluorescent nanoparticles in the body of medaka fish during embryonic development and adulthood. The results obtained from the study showed that 39.4-nm particles could shift into the yolk and gallbladder during embryonic development. In addition, particles were detected in the brain, testis, liver, blood, and, especially, the gill and intestine of adult fish. In light of these results, the author suggested that nanoparticles cross the blood–brain barrier to reach the brain. The study contains very valuable information and remains frequently cited as evidence that nanoparticles cross the blood–brain barrier, but it has some limitations that have not previously been described.

The blood–brain barrier is a complex cellular system that allows the passage of essential nutrients for brain cells and at the same time protects the brain from harmful substances that may be present in the blood (Chen and Liu 2012; O’Brown et al. 2018). This barrier, which controls the passage of substances between blood and brain cells both enzymatically and physically, essentially consists of endothelial cells and tight junctions (Figure 1). This complex cellular system, which contains the capillaries that feed and carry oxygen to the brain cells, must be positioned to be dispersed throughout the brain and at a certain distance from the brain cells (Figure 1). In other words, this barrier is localized between the brain cells and the vessels feeding these cells (O’Brown et al. 2018; Schlageter et al. 1999; Tajes et al. 2014). Therefore, concluding that a particle detected in the brain tissue has crossed the blood–brain barrier requires rigorous evidence (via imaging or other detection method) that the particle has crossed the vessel lumen (i.e., is extravascular) (Yang et al. 2004).

In the study by Kashiwada (2006), the presence of particles in the brain was determined by the intensity of fluorescent signals without information on whether these signals derived from the extravascular or intravascular space. As a result, the author’s central conclusions that “These results suggest that nanoparticles are capable of penetrating the blood–brain barrier and that they eventually reach the brain” and that “[n]anoparticles penetrated the blood–brain barrier to reach the brain, although the amounts of nanoparticles that reached the brain were low” are not justified.