Site-Specific Antibody鈥揚olymer Conjugates for siRNA Delivery

详细信息    查看全文

• 作者：Hua Lu ; Danling Wang ; Stephanie Kazane ; Tsotne Javahishvili ; Feng Tian ; Frank Song ; Aaron Sellers ; Barney Barnett ; Peter G. Schultz
• 刊名：Journal of the American Chemical Society
• 出版年：2013
• 出版时间：September 18, 2013
• 年：2013
• 卷：135
• 期：37
• 页码：13885-13891
• 全文大小：323K
• 年卷期：v.135,no.37(September 18, 2013)
• ISSN：1520-5126

文摘

We describe here the development of site-specific antibody鈥損olymer conjugates (APCs) for the selective delivery of small interference RNAs (siRNAs) to target cells. APCs were synthesized in good yields by conjugating an aminooxy-derivatized cationic block copolymer to an anti-HER2 Fab or full-length IgG by means of genetically encoded p-acetyl phenylalanine (pAcF). The APCs all showed binding affinity comparable to that of HER2 as their native counterparts and no significant cellular cytotoxicity. Mutant S202-pAcF Fab and Q389-pAcF IgG polymer conjugates specifically delivered siRNAs to HER2⁺ cells and mediated potent gene silencing at both the mRNA and protein levels. However, a mutant A121-pAcF IgG polymer conjugate, despite its high binding affinity to HER2 antigen, did not induce a significant RNA interference response in HER2⁺ cells, presumably due to steric interference with antigen binding and internalization. These results highlight the importance of conjugation site on the activity of antibody鈥損olymer-based therapeutics and suggest that such chemically defined APCs may afford a useful targeted delivery platform for siRNAs or other nucleic acid-based therapies.