Abstract
Polymers are widely used as non-viral carriers for siRNA delivery, but concern has also arisen in their limited efficacy and inherent toxicity. Whilst many of previous efforts have been documented towards improving the performance of polymers via chemical modifications, the structure-activity relationships (SAR) of these ligand-modified polymers are not well understood. To address this issue, we systemically prepared a library of surface-engineered dendrimers (>300) as the screening pool to discover efficient siRNA carriers. The modified ligands include alkyls and fluoroalkyls, amino acids, benzene derivatives and heterocyclic compounds. Gene silencing results showed that the lead material shows excellent efficacy even in hard-to-transfect cells such as mesenchymal stem cells. The SAR studies revealed that ligands containing appropriate hydrophobicity, or ligands with both hydrophobic and functional atoms/groups are essential for polymers to achive efficient knockdown efficacy. A second-generation library designed based on the above principles further confirms the proposed design criteria. The results enable the future rational design of potent siRNA carriers.
Highlights
The discovery of small interfering RNA has offered new avenues in the clinical treatment of various diseases, such as cancers, virus infections, obesity, neurodegenerative diseases, and metabolic skeletal disorders1–5. siRNAs are relatively hydrophilic molecules with anionic charges
We prepared a library of ligand-modified polymers, which is used as a screening pool to discover siRNA carriers which can achieve efficient gene silencing in the absence of helper lipids
Gene silencing efficacy of the resulting materials was first tested on HeLa-luc cells (HeLa cells stably expressing a firefly luciferase gene) using a siRNA targeting luciferase
Summary
The discovery of small interfering RNA (siRNA) has offered new avenues in the clinical treatment of various diseases, such as cancers, virus infections, obesity, neurodegenerative diseases, and metabolic skeletal disorders1–5. siRNAs are relatively hydrophilic molecules with anionic charges. To achieve efficient and low toxic siRNA delivery, the polymers need to be functionalized with various ligands including lipids[21], sugars[22], peptides[23], cyclodextrins[24], fluorous chains[25], amino acids[26], and nanoparticles[27]. Despite these impressive efforts, the rational design of efficient siRNA carriers remains challenging. By introduction of alkyl chains onto low molecular weight polymers, they discovered a list of efficient amphiphilic materials with high siRNA delivery efficacy in vitro and in vivo[38,39,40]. These unique properties make dendrimer an ideal candidate in the study of SAR of ligand-modified polymers
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