Crossing the blood–brain–barrier with transferrin conjugated carbon dots: A zebrafish model study

Abstract

Drug delivery to the central nervous system (CNS) in biological systems remains a major medical challenge due to the tight junctions between endothelial cells known as the blood-brain-barrier (BBB). Here we use a zebrafish model to explore the possibility of using transferrin-conjugated carbon dots (C-Dots) to ferry compounds across the BBB. C-Dots have previously been reported to inhibit protein fibrillation, and they are also used to deliver drugs for disease treatment. In terms of the potential medical application of C-Dots for the treatment of CNS diseases, one of the most formidable challenges is how to deliver them inside the CNS. To achieve this in this study, human transferrin was covalently conjugated to C-Dots. The conjugates were then injected into the vasculature of zebrafish to examine the possibility of crossing the BBB in vivo via transferrin receptor-mediated endocytosis. The experimental observations suggest that the transferrin-C-Dots can enter the CNS while C-Dots alone cannot.

Biocompatible and blood–brain barrier permeable carbon dots for inhibition of Aβ fibrillation and toxicity, and BACE1 activity

“…24,25 All characterizations using ultra violet-visible (UV-vis), mass spectrometry, and transmission electron microscopy (TEM) were consistent with previous reported results. Initially, a fluorescence resonance energy transfer (FRET) assay was employed to examine the effect of C-Dots on the inhibition of BACE1 activity.…”

“…To obtain more details about the Aβ fibrillation by C-Dots, molecular dynamics simulations with the Martini coarse-grained force field 26 were performed to study the interaction between C-Dots and Aβ monomers, which has been a valuable tool for the study of Aβ peptides. 27–29 In this study, the surface of C-Dots has a high oxygen content, 24 which indicates high hydrophilicity. In order to see the role of the hydrophilic surface, C-Dot models with both hydrophilic and hydrophobic C-Dots were constructed.…”

“…Previously, human transferrin (HT) has been utilized to deliver the C-Dots across the BBB in a zebrafish model. 24 Inspired by this, C-Dots were used as a potential drug candidate for the design of new BBB-permeable nanomaterials for application in AD treatment for the first time. C-Dots possess large surface to volume ratios, and this low dimensionality nanomaterial is expected to redirect the partially unfolded Aβ by increasing the fibril steric hindrance as a result of their interaction with the Aβ monomer (Figure 1).…”

“…To achieve this aim, HT was previously used to deliver the C-Dots across the BBB in a zebrafish model. 24 In this research, the same procedure was followed. Briefly, C-Dots loaded with HT were injected into the heart of anesthetized zebrafish at five days post-fertilization (dpf), where the maturation of its BBB developed as early as 3 dpf.…”

“…Briefly, C-Dots loaded with HT were injected into the heart of anesthetized zebrafish at five days post-fertilization (dpf), where the maturation of its BBB developed as early as 3 dpf. 24 Confocal fluorescence microscopy was used to examine the brain sections of zebrafish in three dimensions by measuring the normalized fluorescence intensity after 5 h injections. Figure 4a demonstrates that the C-Dots can target the forebrain of zebrafish, and this is compared to the dorsal (Figure 4b) and the ventral (Figure 4c) section images.…”