RNA interference is a very useful tool for clinical treatment as well as mechanistic studies of leukemia. However, leukemia cells are known as hard-to-transfected by non-virus carriers. The low capacity of endocytosis and lysosomal escape of synthetic carriers are two obstacles for successful RNAi in leukemia cells. In this work, we established a universal powerful strategy for mediating effective RNAi in different types of leukemia cells by sequentially using spermine-modified pullulan (PS) as siRNA carrier and desloratadine (DL) to promote the lysosomal escape. It was shown that the complex of PS and siRNA could be largely internalized by human T-cell acute lymphoblastic leukemia cells, acute myeloid leukemia cells and chronic myeloid leukemia cells in serum-containing media, and the internalized complex was able to escape from the lysosomes by the aid of DL, resulting in effective RNAi against the key genes for the different leukemia cells.
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.
危险品化学品经营许可证（带存储）