Screening of efficient siRNA carriers in a library of surface-engineered dendrimers.
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.
Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai 200241, P. R. China.
Hongmei
H
Liu
Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai 200241, P. R. China.
Hong
H
Chang
Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai 200241, P. R. China.
Jia
J
Lv
Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai 200241, P. R. China.
Cong
C
Jiang
Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai 200241, P. R. China.
Zhenxi
Z
Li
Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai 200241, P. R. China.
Fei
F
Wang
Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai 200241, P. R. China.
Hui
H
Wang
Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai 200241, P. R. China.
Mingming
M
Wang
Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai 200241, P. R. China.
Chongyi
C
Liu
Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai 200241, P. R. China.
Xinyu
X
Wang
Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai 200241, P. R. China.
Naimin
N
Shao
Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai 200241, P. R. China.
Bingwei
B
He
Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai 200241, P. R. China.
Wanwan
W
Shen
Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai 200241, P. R. China.
Qiang
Q
Zhang
Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai 200241, P. R. China.
Yiyun
Y
Cheng
D000818:Animals; D002460:Cell Line; D050091:Dendrimers / Q000737:chemistry* / Q000378:metabolism*; D004337:Drug Carriers / Q000737:chemistry* / Q000378:metabolism*; D020868:Gene Silencing; D006801:Humans; D008403:Mass Screening; D051379:Mice; D034741:RNA, Small Interfering / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014162:Transfection
D050091:Dendrimers; D004337:Drug Carriers; C104700:PAMAM Starburst; D034741:RNA, Small Interfering