Lipophilic Peptide Dendrimers for Delivery of Splice-Switching Oligonucleotides

Daralnakhla, Haneen; Saher, Osama; Zamolo, Susanna; Bazaz, Safa; Bost, Jeremy; Heitz, Marc; Lundin, Karin E.; Andaloussi, Samir El; Darbre, Tamis; Reymond, Jean‐Louis; Zain, Rula; Smith, C. I. Edvard

doi:10.3390/pharmaceutics13010116

Cited by 6 publications

(7 citation statements)

References 51 publications

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“…Dendrimer systems can also incorporate lipid or polymers to obtain greater efficacy. It has been demonstrated that transfection was enhanced by the addition of a polyol to the lipid/dendrimer hybrid ( 49 ) or a polymer excipient, such as Polyvinylalcohol 18 (PVA 18) ( 50 ).…”

Section: Methodsmentioning

confidence: 99%

Non-viral Vectors in Gene Therapy: Recent Development, Challenges, and Prospects

Gao

2021

AAPS J

239

161

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Gene therapy has been experiencing a breakthrough in recent years, targeting various specific cell groups in numerous therapeutic areas. However, most recent clinical studies maintain the use of traditional viral vector systems, which are challenging to manufacture cost-effectively at a commercial scale. Non-viral vectors have been a fast-paced research topic in gene delivery, such as polymers, lipids, inorganic particles, and combinations of different types. Although non-viral vectors are low in their cytotoxicity, immunogenicity, and mutagenesis, attracting more and more researchers to explore the promising delivery system, they do not carry ideal characteristics and have faced critical challenges, including gene transfer efficiency, specificity, gene expression duration, and safety. This review covers the recent advancement in non-viral vectors research and formulation aspects, the challenges, and future perspectives.

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Section: Methodsmentioning

confidence: 99%

Non-viral Vectors in Gene Therapy: Recent Development, Challenges, and Prospects

Gao

2021

AAPS J

239

161

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“…More recently, peptide dendrimers with covalently attached lipophilic tails showed efficient transfection without lipofectin. 6,7,11,12 Two very efficient third-generation peptide dendrimer sequences, MH18 and MH13 (Figure 1A,B), 10,11 are constituted by leucines and lysines, with a tetra-leucine or two palmitoyl groups as a hydrophobic core, respectively. By changing the chirality of these sequences and performing a few mutations in the sequences, it was possible to modulate the affinity for nucleic acids and their performances as transfecting agents.…”

Section: Introductionmentioning

confidence: 99%

High Charge Density in Peptide Dendrimers is Required to Destabilize Membranes: Insights into Endosome Evasion

Rodrigues,

Darbre,

Machuqueiro

2024

J. Chem. Inf. Model.

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Peptide dendrimers are a type of branched, symmetric, and topologically well-defined molecule that have already been used as delivery systems for nucleic acid transfection. Several of the most promising sequences showed high efficiency in many key steps of transfection, namely, binding siRNA, entering cells, and evading the endosome. However, small changes to the peptide dendrimers, such as in the hydrophobic core, the amino acid chirality, or the total available charges, led to significantly different experimental results with unclear mechanistic insights. In this work, we built a computational model of several of those peptide dendrimers (MH18, MH13, and MH47) and some of their variants to study the molecular details of the structure and function of these molecules. We performed CpHMD simulations in the aqueous phase and in interaction with a lipid bilayer to assess how conformation and protonation are affected by pH in different environments. We found that while the different peptide dendrimer sequences lead to no substantial structural differences in the aqueous phase, the total charge and, more importantly, the total charge density are key for the capacity of the dendrimer to interact and destabilize the membrane. These dendrimers become highly charged when the pH changes from 7.5 to 4.5, and the presence of a high charge density, which is decreased for MH47 that has four fewer titratable lysines, is essential to trigger membrane destabilization. These findings are in excellent agreement with the experimental data and help us to understand the high efficiency of some dendrimers and why the dendrimer MH47 is unable to complete the transfection process. This evidence provides further understanding of the mode of action of these peptide dendrimers and will be pivotal for the future design of new sequences with improved transfection capabilities.

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“…In addition to chemical modification, a more generic approach to improve TNA performance involves the use of cationic and/or lipophilic transfection reagents, which increase cell membrane penetration and cytosolic accumulation of oligonucleotides. [ 30–32 ] Furthermore, functionalized nanocarriers, modified with, for example, targeting agents and cell penetrating enhancers could increase their intracellular delivery and efficacy, thereby reducing dosages and potential immunogenicity. [ 33–37 ]…”

Section: Introductionmentioning

confidence: 99%

Cowpea Chlorotic Mottle Virus‐Like Particles as Potential Platform for Antisense Oligonucleotide Delivery in Posterior Segment Ocular Diseases

Pretto

Tang

Chen

et al. 2021

Macromolecular Bioscience

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Due to its small size, easy accessibility and immune privileged environment, the eye represents an ideal target for therapeutic nucleic acids in the treatment of posterior segment ocular diseases, such as age‐related macular degeneration (AMD). Among nanocarriers that can be used to achieve nucleic acid delivery, virus‐like particles (VLPs) obtained from the Cowpea chlorotic mottle virus (CCMV) are an appealing platform, because of their loading capacity, ease of manufacture and amenability for functionalization. Herein, antisense oligonucleotide‐loaded CCMV nanoparticles, intended for intravitreal injection, are evaluated for selective silencing of miR‐23, an important target in AMD. CCMV nanoparticles loaded with anti‐miR‐23 locked nucleic acid and stabilized using the 3,3′‐dithiobis(sulfosuccinimidyl propionate) (DTSSP) cross‐linker, are assembled in vitro with a loading efficiency up to 80%. VLPs are found to be stable at 37 °C in the vitreous humor up to 24 hours. Nanoparticle cytotoxicity, cellular uptake and transfection efficacy are evaluated in endothelial cells. Selective miRNA down‐regulation is achieved by the loaded CCMV VLPs both in absence and presence of Lipofectamine, with efficacies of ≈40% and more than 80%, respectively. The authors' findings pave the way for the future development of CCMV nanoparticles as oligonucleotide delivery platform to treat posterior segment ocular diseases.

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Lipophilic Peptide Dendrimers for Delivery of Splice-Switching Oligonucleotides

Cited by 6 publications

References 51 publications

Non-viral Vectors in Gene Therapy: Recent Development, Challenges, and Prospects

Non-viral Vectors in Gene Therapy: Recent Development, Challenges, and Prospects

High Charge Density in Peptide Dendrimers is Required to Destabilize Membranes: Insights into Endosome Evasion

Cowpea Chlorotic Mottle Virus‐Like Particles as Potential Platform for Antisense Oligonucleotide Delivery in Posterior Segment Ocular Diseases

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