Faculty, Staff and Student Publications
Publication Date
5-11-2024
Journal
Nature Communications
Abstract
Despite advances in active drug targeting for blood-brain barrier penetration, two key challenges persist: first, attachment of a targeting ligand to the drug or drug carrier does not enhance its brain biodistribution; and second, many brain diseases are intricately linked to microcirculation disorders that significantly impede drug accumulation within brain lesions even after they cross the barrier. Inspired by the neuroprotective properties of vinpocetine, which regulates cerebral blood flow, we propose a molecular library design centered on this class of cyclic tertiary amine compounds and develop a self-enhanced brain-targeted nucleic acid delivery system. Our findings reveal that: (i) vinpocetine-derived ionizable-lipidoid nanoparticles efficiently breach the blood-brain barrier; (ii) they have high gene-loading capacity, facilitating endosomal escape and intracellular transport; (iii) their administration is safe with minimal immunogenicity even with prolonged use; and (iv) they have potent pharmacologic brain-protective activity and may synergize with treatments for brain disorders as demonstrated in male APP/PS1 mice.
Keywords
Animals, Vinca Alkaloids, Nanoparticles, Blood-Brain Barrier, Mice, Cerebrovascular Circulation, Male, Brain, Humans, Neuroprotective Agents, Mice, Inbred C57BL, Tissue Distribution, Drug Delivery Systems, Mice, Transgenic, Nanoparticles, Nucleic-acid therapeutics, Biomedical engineering, Drug delivery
DOI
10.1038/s41467-024-48461-4
PMID
38734698
PMCID
PMC11088666
PubMedCentral® Posted Date
5-11-2024
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Included in
Bioinformatics Commons, Biomedical Informatics Commons, Genetic Phenomena Commons, Medical Genetics Commons, Oncology Commons