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

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