Crossing the blood-brain barrier (BBB) is a great challenge for delivery of highly charged macromolecules such as nucleic acids and proteins to the brain. Cell-penetrating peptides (CPPs) are promising vectors to deliver various cargoes ranging from small molecules to large molecules such as antibodies, proteins, and nucleic acids. The BBB limits the passage of all large molecules to central nervous system (CNS), thus, CPP is a potential vector to use for oligonucleotide delivery across the BBB. In paper I, various CPPs were covalently conjugated with two different glioma-targeting peptides, glioma-homing peptide (gHo) and angiopep-2 (ANG). PepFect 32 (PF32), a conjugation between truncated PepFect 14 and ANG, was the most efficient vector to deliver plasmid DNA (pDNA) across a setup in vitro model of the BBB and showed the highest transfection in glioma cells. LRP-1 receptors, which are over-expressed in brain endothelial cells and glioma cells, were speculated to mediate the transcytosis of PF32:pDNA complexes across the BBB model since the ANG could target to LRP-1. In paper II, scavenger receptors class A and B (SCARA3, SCARA5, and SR-BI) were found to be expressed in the brain endothelial cells. Inhibition of these scavenger receptors led to a reduction of the transfection of PF32:pDNA complexes in the brain endothelial cells. Therefore, in the BBB model scavenger receptors also played a vital role as well as LRP-1 in the transport of oligonucleotides in the complex with peptide-based vector PF32.

In conclusion, PF32 is a potential vector to deliver pDNA across the BBB model and target to the glioma cells. The complexes of PF32:pDNA transport across the brain endothelial cells via receptor-mediated endocytosis pathway recognized by scavenger receptors and LRP-1. To improve the specificity and enhance the transport into the brain, the brain-homing devices are considered as a promising strategy for CNS drug delivery.


Dr. Ing-Marie Nilsson, Institutionen för biokemi och biofysik, SU

Professor Kerstin Iverfeldt, Institutionen för neurokemi, SU