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Cited by 35RNA Interference and Gene DeliveryNanoparticle-Based Drug DeliveryBarrier Structure and Function Studies

Synthesis and Evaluation of Parenchymal Retention and Efficacy of a Metabolically Stable O-Phosphocholine-N-docosahexaenoyl-l-serine siRNA Conjugate in Mouse Brain

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Nikan, Mehran, Osborn, Maire F., Coles, Andrew H., Biscans, Annabelle, Godinho, Bruno M.D.C., Haraszti, Reka A., Sapp, Ellen, Echeverria, Dimas +3 more·2017·Bioconjugate Chemistry
DOI 10.1021/acs.bioconjchem.7b00226PMC PMC5578421
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Abstract

Ligand-conjugated siRNAs have the potential to achieve targeted delivery and efficient silencing in neurons following local administration in the central nervous system (CNS). We recently described the activity and safety profile of a docosahexaenoic acid (DHA)-conjugated, hydrophobic siRNA (DHA-hsiRNA) targeting Huntingtin (Htt) mRNA in mouse brain. Here, we report the synthesis of an amide-modified, phosphocholine-containing DHA-hsiRNA conjugate (PC-DHA-hsiRNA), which closely resembles the endogenously esterified biological structure of DHA. We hypothesized that this modification may enhance neuronal delivery in vivo. We demonstrate that PC-DHA-hsiRNA silences Htt in mouse primary cortical neurons and astrocytes. After intrastriatal delivery, Htt-targeting PC-DHA-hsiRNA induces ∼80% mRNA silencing and 71% protein silencing after 1 week. However, PC-DHA-hsiRNA did not substantially outperform DHA-hsiRNA under the conditions tested. Moreover, at the highest locally administered dose (4 nmol, 50 μg), we observe evidence of PC-DHA-hsiRNA-mediated reactive astrogliosis. Lipophilic ligand conjugation enables siRNA delivery to neural tissues, but rational design of functional, nontoxic siRNA conjugates for CNS delivery remains challenging.

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Authors
Nikan, M., Osborn, M. F., Coles, A. H., Biscans, A., Godinho, B. M. D. C., Haraszti, R. A., Sapp, E., Echeverria, D., DiFiglia, M., Aronin, N., & Khvorova, A.
Affiliations
  • University of Massachusetts Chan Medical School (US)
  • Massachusetts General Hospital (US)
Corresponding author
  • Osborn, Maire F.
  • Khvorova, Anastasia
ORCID
Venue
Bioconjugate Chemistry
Publisher
American Chemical Society (ACS)
Published
2017-05-10
Volume
28
Issue
6
Pages
1758-1766
ISSN
  • 1043-1802 (ISSN-L)
  • 1520-4812
DOI
10.1021/acs.bioconjchem.7b00226
PMC
PMC5578421
OpenAlex
W2610933455
Cited by
35
References
4
Citations by year
2026: 3 · 2025: 3 · 2024: 1 · 2022: 1 · 2021: 3 · 2020: 3 · 2019: 6 · 2018: 13 · 2017: 2
FWCI
2.68
Type
journal article
Language
en
Open access
Locations
  • Bioconjugate Chemistry (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Center for Advancing Translational Sciences (UH3TR00088803)
  • National Institute of Neurological Disorders and Stroke (F32NS095508, RO1NS038194)
  • CHDI Foundation (A-6119, JSC A6367)
  • National Institute of General Medical Sciences (RO1GM10880302)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
  • Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
  • Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
Keywords
siRNA conjugates, docosahexaenoic acid, phosphorylcholine, reactive astrogliosis, astrocytes, primary cortical neurons, lipophilic ligands
MeSH terms
Huntingtin Protein, Parenchymal Tissue, Animals, Brain, Docosahexaenoic Acids, Drug Stability, Phosphorylcholine, RNA, Messenger, Serine, Drug Delivery Systems, Treatment Outcome, Gene Silencing, RNA Interference, RNA, Small Interfering, Mice

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