Screening of efficient siRNA carriers in a library of surface-engineered dendrimers

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.

Insight Into the Prospects for RNAi Therapy of Cancer

“…The end group can be functionalized; providing a variety of functions. On the surface of the polymer, significantly positive amine functional groups are also found, which are conducive for tight binding with siRNA (Liu et al, 2016). Recently, cationic dendrimers have been studied as carriers for siRNA delivery.…”

“…Genasense can specifically bind to human Bcl-2 mRNA, which leads to the catalytic degradation of Bcl-2 mRNA and reduces the translation of Bcl-2 protein. Therefore, researchers can use mRNA degradation strategies and small inhibitory molecules for targeted Bcl-2 therapy in a variety of cancers, such as breast cancer, colon cancer, and prostate cancer ( Li et al, 2016 ). Moreover, preclinical studies have shown that the combination of Bcl-2 antisense and chemotherapy improved the anti-tumour response, thereby increasing the apoptosis of tumor cells and improving the survival rate.…”

Fundamentals of siRNA and miRNA therapeutics and a review of targeted nanoparticle delivery systems in breast cancer

“…Dendrimers have positively charged amine functionalities at the surface that enable condensation of negatively charged siRNA molecules through electrostatic interactions. They also have tertiary amine groups in the interior that can be protonated in acidic endosomes to initiate the proton sponge effect (Liu et al 2016). The most common de ndrimer use d for siRNA delive ry systems is poly(amidoamine) (PAMAM) (Gu et al 2015;Sun et al 2017b), a cationic polymer that has good pH buffering capability.…”

New Advances in General Biomedical Applications of PAMAM Dendrimers

“…Liu and colleagues [ 102 ] published a library of surface-engineered dendrimers, which can be applied as siRNA carriers. Structure–activity relationship (SAR) studies demonstrated that hydrophobic ligands—such as aliphatic chains, aromatic rings, fluorine, and bromine atoms—are fundamental for polymers, since they may provide high levels of gene silencing efficacy.…”