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ApoE-functionalization of nanoparticles for targeted brain delivery: a feasible method for polyplexes?

The blood-brain barrier (BBB) poses a major obstacle in the treatment of all types of central nervous system (CNS) diseases. Small interfering RNA (siRNA) offers in principle a promising therapeutic approach by downregulating disease-related genes via RNA interference. However, the BBB is a formidab...

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Main Authors: Hartl, Natascha Verena (Author) , Gabold, Bettina (Author) , Uhl, Philipp (Author) , Kromer, Adrian (Author) , Xiao, Ximian (Author) , Fricker, Gert (Author) , Mier, Walter (Author) , Liu, Runhui (Author) , Merkel, Olivia (Author)
Format: Article (Journal)
Language:English
Published: 12 December 2023
In: Drug Delivery and Translational Research
Year: 2024, Volume: 14, Issue: 6, Pages: 1660-1677
ISSN:2190-3948
DOI:10.1007/s13346-023-01482-w
Online Access:Resolving-System, kostenfrei, Volltext: https://doi.org/10.1007/s13346-023-01482-w
Verlag, kostenfrei, Volltext: https://link.springer.com/article/10.1007/s13346-023-01482-w
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Author Notes:Natascha Hartl, Bettina Gabold, Philipp Uhl, Adrian Kromer, Ximian Xiao, Gert Fricker, Walter Mier, Runhui Liu, Olivia M. Merkel

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520 |a The blood-brain barrier (BBB) poses a major obstacle in the treatment of all types of central nervous system (CNS) diseases. Small interfering RNA (siRNA) offers in principle a promising therapeutic approach by downregulating disease-related genes via RNA interference. However, the BBB is a formidable barrier for macromolecules such as nucleic acids. In an effort to develop a brain-targeted strategy for siRNA delivery systems formed by electrostatic interactions with cationic polymers (polyplexes (PXs)), we investigated the suitability of the well-known surfactant-based approach for Apolipoprotein E (ApoE)-functionalization of nanoparticles (NPs). The aim of this present work was to investigate if ApoE coating of siRNA PXs formed with cationic branched 25-kDa poly(ethyleneimine) (b-PEI) and nylon-3 polymers without or after precoating with polysorbate 80 (PS 80) would promote successful delivery across the BBB. We utilized highly hydrophobic NM0.2/CP0.8 nylon-3 polymers to evaluate the effects of hydrophobic cyclopentyl (CP) subunits on ApoE binding efficacy and observed successful ApoE binding with and without PS 80 precoating to the nylon-3 but not the PEI polyplexes. Accordingly, ApoE-coated nylon-3 polyplexes showed significantly increased uptake and gene silencing in U87 glioma cells but no benefit in vivo. In conclusion, further optimization of ApoE-functionalized polyplexes and more sophisticated in vitro models are required to achieve more successful in vitro-in vivo translation in future approaches. 
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