Nose-to-brain delivery of enveloped RNA - cell permeating peptide nanocomplexes for the treatment of neurodegenerative diseases

Direct nose-to-brain (N-to-B) delivery enables the rapid transport of drugs to the brain, while minimizing systemic exposure. The objective of this work was to engineer a nanocarrier intended to enhance N-to-B delivery of RNA and to explore its potential utility for the treatment of neurological dis...

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Bibliographic Details
Published in:Biomaterials 2020-02, Vol.230, p.119657-119657, Article 119657
Main Authors: Samaridou, Eleni, Walgrave, Hannah, Salta, Evgenia, Álvarez, David Moreira, Castro-López, Vanessa, Loza, Mabel, Alonso, Maria José
Format: Article
Language:English
Subjects:
Administration, Intranasal
Animals
Brain
Brain delivery
Cell-penetrating peptide
Cricetinae
Cricetulus
Drug Delivery Systems
Mice
miRNA
Nanocomplex
Nanoparticles
Neurodegenerative Diseases
Nose-to-Brain administration
Octaarginine
Peptides
Polyglutamic Acid
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Summary:Direct nose-to-brain (N-to-B) delivery enables the rapid transport of drugs to the brain, while minimizing systemic exposure. The objective of this work was to engineer a nanocarrier intended to enhance N-to-B delivery of RNA and to explore its potential utility for the treatment of neurological disorders. Our approach involved the formation of electrostatically driven nanocomplexes between a hydrophobic derivative of octaarginine (r8), chemically conjugated with lauric acid (C12), and the RNA of interest. Subsequently, these cationic nanocomplexes were enveloped (enveloped nanocomplexes, ENCPs) with different protective polymers, i.e. polyethyleneglycol - polyglutamic acid (PEG-PGA) or hyaluronic acid (HA), intended to enhance their stability and mucodiffusion across the olfactory nasal mucosa. These rationally designed ENCPs were produced in bulk format and also using a microfluidics-based technique. This technique enabled the production of a scalable nanoformulation, exhibiting; (i) a unimodal size distribution with a tunable mean size, (ii) the capacity to highly associate (100%) and protect RNA from degradation, (iii) the ability to preserve its physicochemical properties in biorelevant media and prevent the premature RNA release. Moreover, in vitro cell culture studies showed the capacity of ENCPs to interact and be efficiently taken-up by CHO cells. Finally, in vivo experiments in a mouse model of Alzheimer's disease provided evidence of a statistically significant increase of a potentially therapeutic miRNA mimic in the hippocampus area and its further effect on two mRNA targets, following its intranasal administration. Overall, these findings stress the value of the rational design of nanocarriers towards overcoming the biological barriers associated to N-to-B RNA delivery and reveal their potential value as therapeutic strategies in Alzheimer's disease.
ISSN:0142-9612
1878-5905
DOI:10.1016/j.biomaterials.2019.119657