Design and evaluation of ionizable peptide amphiphiles for siRNA delivery

Neuberg, Patrick; Wagner, Alain; Rémy, Jean-Serge; Kichler, Antoine

doi:10.1016/j.ijpharm.2019.05.052

Cited by 10 publications

(10 citation statements)

References 30 publications

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“…Interestingly, a higher concentration of glutathione presents exactly in tumor cells compared to normal ones that make the CLP usage promising for tumor gene therapy [30]. Peptides modified with histidine residues can destroy endosomal membrane due to the imidazole protonation facilitating DNA diffusion from endosome to cytosol by proton sponge effect [31][32][33]. By using ligand-modified peptides, DNA can be selectively delivered to the tumors what can reduce associated severe side effects, e.g., unspecific toxicity.…”

Section: Introductionmentioning

confidence: 99%

Development of iRGD-Modified Peptide Carriers for Suicide Gene Therapy of Uterine Leiomyoma

et al. 2021

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Uterine leiomyoma (UL) is one of the most common benign tumors in women that often leads to many reproductive complications. Suicide genetherapy was suggested as a promising approach for UL treatment. In the present study, we describe iRGD ligand-conjugated cysteine-rich peptide carrier RGD1-R6 for targeted DNA delivery to αvβ3 integrin-expressing primary UL cells. The physico-chemical properties, cytotoxicity, transfection efficiency and specificity of DNA/RGD1-R6 polyplexes were investigated. TheHSV-1thymidine kinase encoding plasmid delivery to PANC-1pancreatic carcinoma cells and primary UL cells resulted in significant suicide gene therapy effects. Subsequent ganciclovir treatment decreased cells proliferative activity, induced of apoptosis and promoted cells death.The obtained results allow us to concludethatthe developed RGD1-R6 carrier can be considered a promising candidate for suicide gene therapy of uterine leiomyoma.

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Section: Introductionmentioning

confidence: 99%

Development of iRGD-Modified Peptide Carriers for Suicide Gene Therapy of Uterine Leiomyoma

et al. 2021

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“…Another amino acid which appeared to be important for promoting the translocation properties of these CPPs was the tryptophan residue [35]. This has been highlighted in a study where a tryptophan residue was replaced by a tyrosine leading to the loss of cellular transfection of siRNAs despite the formation of much smaller nanoparticles [20]. The importance of tryptophan residues has been also con rmed in a recent publication showing the proper internalization of a Penetratin analogue only composed of arginine and tryptophan [36].…”

Section: Introductionmentioning

confidence: 91%

“…Others groups also investigated the effect of coupling hydrophobic moieties to the peptide moieties in order to promote the siRNA delivery. These include the work of Neuberg and co-workers who coupled either a simple amino acid such as histidine or dipeptides to a dioctadecylamine tail through a hydrophilic linker [20]. They evidenced better vectors for siRNA transfection upon this hydrophobization.…”

Section: Introductionmentioning

confidence: 99%

WRAP-based nanoparticles for siRNA delivery: A SAR study and a comparison with lipid-based transfection reagents.

Konate

Josse

Tasic

et al. 2020

Preprint

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Recently, we designed novel amphipathic cell-penetrating peptides, called WRAP, able to transfer efficiently siRNA molecules into cells. In order to gain more information about the relationship between amino acid composition, nanoparticle formation and cellular internalization of these peptides composed of only three amino acids (leucine, arginine and tryptophan), we perform a structure activity relationship (SAR) study. First, we compared our WRAP1 and WRAP5 peptides with the C6M1 peptide also composed of the same three amino acids and showing similar behaviors in siRNA transfection. Afterwards, to further define the main determinants in the WRAP activity, we synthesized 13 new WRAP analogues harboring different modifications like the number and location of leucine and arginine residues, the relative location of tryptophan residues, as well as the role of the α-helix formation upon proline insertions within the native WRAP sequence. After having compare the ability of these peptides to form peptide-based nanoparticles (PBNs) or not using different biophysical methods (circular dichroism, dynamic light scattering, gel shift assay) and to induce a targeted gene silencing (luciferase assay) in cells, we were able to establish the main sequential requirements of the amino acid composition of the WRAP peptides to maintain a good siRNA transfection efficacy. In addition, upon measuring the WRAP-based siRNA transfection ability into cells compared to several non-peptide transfection agents available on the markets, we confirmed that WRAP peptides induced an equivalent level of targeted gene silencing but in most of the cases with significant lower cell toxicity as clearly shown in clonogenic assays.

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“…Initial pioneering work identified the required number of cationic amino acids as lysine, arginine or ornithine in precise defined macromolecular structures [ 32 ]. The incorporation of cysteines improved the polyplexes stability by disulfide cross-linking, and the incorporation of endosomal-buffering histidine [ 33 ] or membrane-destabilizing peptides [ 34 , 35 ] enhanced nucleic acid delivery efficiency by improving their endosomal escape capacity.…”

Section: Sequence-defined Macromolecular Carriersmentioning

confidence: 99%

Non-Viral Targeted Nucleic Acid Delivery: Apply Sequences for Optimization

Wang

Wagner

2020

Pharmaceutics

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In nature, genomes have been optimized by the evolution of their nucleic acid sequences. The design of peptide-like carriers as synthetic sequences provides a strategy for optimizing multifunctional targeted nucleic acid delivery in an iterative process. The optimization of sequence-defined nanocarriers differs for different nucleic acid cargos as well as their specific applications. Supramolecular self-assembly enriched the development of a virus-inspired non-viral nucleic acid delivery system. Incorporation of DNA barcodes presents a complementary approach of applying sequences for nanocarrier optimization. This strategy may greatly help to identify nucleic acid carriers that can overcome pharmacological barriers and facilitate targeted delivery in vivo. Barcode sequences enable simultaneous evaluation of multiple nucleic acid nanocarriers in a single test organism for in vivo biodistribution as well as in vivo bioactivity.

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Design and evaluation of ionizable peptide amphiphiles for siRNA delivery

Cited by 10 publications

References 30 publications

Development of iRGD-Modified Peptide Carriers for Suicide Gene Therapy of Uterine Leiomyoma

Development of iRGD-Modified Peptide Carriers for Suicide Gene Therapy of Uterine Leiomyoma

WRAP-based nanoparticles for siRNA delivery: A SAR study and a comparison with lipid-based transfection reagents.

Non-Viral Targeted Nucleic Acid Delivery: Apply Sequences for Optimization

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