Design of a peptide-based vector, PepFect6, for efficient delivery of siRNA in cell culture and systemically in vivo.
Samir El Andaloussi,Taavi Lehto,Imre Mäger,Katri Rosenthal-Aizman,Iulian I. Oprea,Oscar E. Simonson,Helena Sork,Kariem Ezzat,Dana Copolovici,Kaido Kurrikoff,Joana R Viola,Eman M. Zaghloul,Rannar Sillard,Henrik J. Johansson,Fatouma Said Hassane,Peter Guterstam,Julia Suhorutsenko,Pedro Moreno,Nikita Oskolkov,Jonas Hälldin,Ulf Tedebark,Andres Metspalu,Bernard Lebleu,Janne Lehtiö,C. I. Edvard Smith,Ülo Langel +25 more
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TLDR
A novel CPP, PepFect 6 (PF6), comprising the previously reported stearyl-TP10 peptide, having pH titratable trifluoromethylquinoline moieties covalently incorporated to facilitate endosomal release is presented, implying that the peptides, in addition to having utility for RNAi screens in vitro, displays therapeutic potential.Abstract:
While small interfering RNAs (siRNAs) have been rapidly appreciated to silence genes, efficient and non-toxic vectors for primary cells and for systemic in vivo delivery are lacking. Several siRNA-delivery vehicles, including cell-penetrating peptides (CPPs), have been developed but their utility is often restricted by entrapment following endocytosis. Hence, developing CPPs that promote endosomal escape is a prerequisite for successful siRNA implementation. We here present a novel CPP, PepFect 6 (PF6), comprising the previously reported stearyl-TP10 peptide, having pH titratable trifluoromethylquinoline moieties covalently incorporated to facilitate endosomal release. Stable PF6/siRNA nanoparticles enter entire cell populations and rapidly promote endosomal escape, resulting in robust RNAi responses in various cell types (including primary cells), with minimal associated transcriptomic or proteomic changes. Furthermore, PF6-mediated delivery is independent of cell confluence and, in most cases, not significantly hampered by serum proteins. Finally, these nanoparticles promote strong RNAi responses in different organs following systemic delivery in mice without any associated toxicity. Strikingly, similar knockdown in liver is achieved by PF6/siRNA nanoparticles and siRNA injected by hydrodynamic infusion, a golden standard technique for liver transfection. These results imply that the peptide, in addition to having utility for RNAi screens in vitro, displays therapeutic potential.read more
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Conflict of interest statement. None declared.
TL;DR: It is found that women over 50 are more likely to have a family history of diabetes, especially if they are obese, than women under the age of 50.
Journal ArticleDOI
Image-based analysis of lipid nanoparticle–mediated siRNA delivery, intracellular trafficking and endosomal escape
Jerome Gilleron,William Querbes,Anja Zeigerer,Anna Borodovsky,Giovanni Marsico,Undine Schubert,Kevin Manygoats,Sarah Seifert,Cordula Andree,Martin Stöter,Hila Epstein-Barash,Ligang Zhang,Victor Koteliansky,Kevin Fitzgerald,Eugenio Fava,Marc Bickle,Yannis Kalaidzidis,Akin Akinc,Martin Maier,Marino Zerial +19 more
TL;DR: It is estimated that escape of siRNAs from endosomes into the cytosol occurs at low efficiency (1–2%) and only during a limited window of time when the LNPs reside in a specific compartment sharing early and late endosomal characteristics.
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Advances in oligonucleotide drug delivery
TL;DR: An overview of oligonucleotide-based drug platforms is provided, focusing on key approaches — including chemical modification, bioconjugation and the use of nanocarriers — which aim to address the delivery challenge.
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Cell-Penetrating Peptides : Design, Synthesis, and Applications
TL;DR: The intrinsic property of cell-penetrating peptides to deliver therapeutic molecules to cells and tissues in a nontoxic manner has indicated that they may be potential components of future drugs and disease diagnostic agents.
Journal ArticleDOI
Cell-Penetrating Peptides: From Basic Research to Clinics
TL;DR: In this article, cell-penetrating peptides (CPPs) have been used to increase medicament concentrations in areas that are difficult to access, which can transport into the cell a wide variety of biologically active conjugates.
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