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Review
. 2015 Jun 29:87:52-67.
doi: 10.1016/j.addr.2015.02.008. Epub 2015 Mar 4.

Delivery of therapeutic oligonucleotides with cell penetrating peptides

Affiliations
Review

Delivery of therapeutic oligonucleotides with cell penetrating peptides

Prisca Boisguérin et al. Adv Drug Deliv Rev. .

Abstract

Oligonucleotide-based drugs have received considerable attention for their capacity to modulate gene expression very specifically and as a consequence they have found applications in the treatment of many human acquired or genetic diseases. Clinical translation has been often hampered by poor biodistribution, however. Cell-penetrating peptides (CPPs) appear as a possibility to increase the cellular delivery of non-permeant biomolecules such as nucleic acids. This review focuses on CPP-delivery of several classes of oligonucleotides (ONs), namely antisense oligonucleotides, splice switching oligonucleotides (SSOs) and siRNAs. Two main strategies have been used to transport ONs with CPPs: covalent conjugation (which is more appropriate for charge-neutral ON analogues) and non-covalent complexation (which has been used for siRNA delivery essentially). Chemical synthesis, mechanisms of cellular internalization and various applications will be reviewed. A comprehensive coverage of the enormous amount of published data was not possible. Instead, emphasis has been put on strategies that have proven to be effective in animal models of important human diseases and on examples taken from the authors' own expertise.

Keywords: Antisense oligonucleotides; Cell penetrating peptides; Delivery; Splice switching oligonucleotides; siRNAs.

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Figures

None
Graphical abstract
Fig. 1
Fig. 1
Outline of the HeLa splicing redirection assay. Note that antisense ON (705) needs a delivery method for HeLa cell entry.
Fig. 2
Fig. 2
Schemes showing methods of conjugation of negatively charged ONs to peptides via thiol-maleimide linkage (A and B).
Fig. 3
Fig. 3
Schemes showing peptide–PNA conjugation through a disulphide linkage (A) and peptide–PNA conjugation through a thioether linkage (B).
Fig. 4
Fig. 4
Schemes showing methods of conjugation of peptides to PMO.
Fig. 5
Fig. 5
Immunohistochemical staining of dystrophin following Pip6a–PMO treatment. Dystrophin staining in the tibialis anterior and heart of C57BL/10, untreated mdx and Pip6a–PMO treated mdx mice. The treated cohort received a single, intravenous 12.5 mg/kg dose, and tissues were harvested 2 weeks later.
Fig. 6
Fig. 6
CPP:ON non-covalent complexes and the peptide-based nanoparticle (PBN) strategy.

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