Bazaz, Safa and Lehto, Tõnis and Tops, Rahel and Gissberg, Olof and Gupta, Dhanu and Bestas, Burcu and Bost, Jeremy and Wiklander, Oscar P. B. and Sork, Helena and Zaghloul, Eman M. and Mamand, Doste R. and Hällbrink, Mattias and Sillard, Rannar and Saher, Osama and Ezzat, Kariem and Smith, C. I. Edvard and Andaloussi, Samir EL and Lehto, Taavi (2021) Novel Orthogonally Hydrocarbon-Modified Cell-Penetrating Peptide Nanoparticles Mediate Efficient Delivery of Splice-Switching Antisense Oligonucleotides In Vitro and In Vivo. Biomedicines, 9 (8). p. 1046. ISSN 2227-9059
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Abstract
Splice-switching therapy with splice-switching oligonucleotides (SSOs) has recently proven to be a clinically applicable strategy for the treatment of several mis-splice disorders. Despite this, wider application of SSOs is severely limited by the inherently poor bioavailability of SSO-based therapeutic compounds. Cell-penetrating peptides (CPPs) are a class of drug delivery systems (DDSs) that have recently gained considerable attention for improving the uptake of various oligonucleotide (ON)-based compounds, including SSOs. One strategy that has been successfully applied to develop effective CPP vectors is the introduction of various lipid modifications into the peptide. Here, we repurpose hydrocarbon-modified amino acids used in peptide stapling for the orthogonal introduction of hydrophobic modifications into the CPP structure during peptide synthesis. Our data show that α,α-disubstituted alkenyl-alanines can be successfully utilized to introduce hydrophobic modifications into CPPs to improve their ability to formulate SSOs into nanoparticles (NPs), and to mediate high delivery efficacy and tolerability both in vitro and in vivo. Conclusively, our results offer a new flexible approach for the sequence-specific introduction of hydrophobicity into the structure of CPPs and for improving their delivery properties.
Item Type: | Article |
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Uncontrolled Keywords: | Peptide Nanoparticles, Splice-Switching Antisense Oligonucleotides. |
Subjects: | R Medicine > R Medicine (General) R Medicine > RS Pharmacy and materia medica |
Divisions: | Department of General Biology > Research papers |
Depositing User: | ePrints Depositor |
Date Deposited: | 08 Oct 2024 19:45 |
Last Modified: | 08 Oct 2024 19:45 |
URI: | https://eprints.cihanuniversity.edu.iq/id/eprint/1221 |