Nanoparticle delivery systems to repair brain pathology
April 2, 2015
4:00 PM - 5:00 PM
Many problems with abnormal brain development and neurodegenerative disease could respond to protein therapy but replacing defective brain proteins or introducing SiRNA into the CNS is a daunting task. We have adapted US Naval nanotechnology to devise a new way of getting proteins/peptides into the brain by attaching them to fluorescent nanoparticles (CdSeZnS-Quantum dots) solubilized with a charged polymer and binding the QDs to the 6 histidine residues in a cell-penetrating lipopeptide: WGDap(Palmitoyl)VKIKKP9GGHis6. This lipopeptide promotes both uptake by cells and egress from endosomes, two major hurdles confronting any attempts to correct problems in the brain. In myelinating rat neonatal hippocampal slices we have shown that a negative coat targets the QDs to neurons whereas a positive coat targets QDs to glia and that digestion of the negatively charged extracellular matrix surrounding glia changes uptake. We can attach any protein via His6 (for example green fluorescent protein or a similarly modified lysosomal hydrolase) and direct them either to neurons or glia. When we microinject QDs at E4 into the spinal canal of embryonic chicks we see no toxicity and uniform labeling of all brain regions, with eventual concentration into the choroid plexus when it develops between E11 and E15. We can also take advantage of the positive charge of the VKIKK to attach modifying negatively charged RNA constructs. This opens up the possibility of delivering proteins or S1RNAs to treat neurodegenerative disease.
Aug 13, 2018
Aug 13, 2018