Conjugation chemistry through acetals toward a dextran-based delivery system for controlled release of siRNA

Cui, Lina; Cohen, Jessica L.; Chu, Crystal K.; Wich, Peter R.; Kierstead, Paul H.; Frechet, Jean

Conjugation chemistry through acetals toward a dextran-based delivery system for controlled release of siRNA

Type

Article

Authors

Cui, Lina
Cohen, Jessica L.
Chu, Crystal K.
Wich, Peter R.
Kierstead, Paul H.
Frechet, Jean

KAUST Department

Chemical Science Program
Office of the VP
Physical Science and Engineering (PSE) Division

Online Publication Date

2012-09-18

Print Publication Date

2012-09-26

Date

2012-09-18

Abstract

New conjugation chemistry for polysaccharides, exemplified by dextran, was developed to enable the attachment of therapeutic or other functional moieties to the polysaccharide through cleavable acetal linkages. The acid-lability of the acetal groups allows the release of therapeutics under acidic conditions, such as that of the endocytic compartments of cells, regenerating the original free polysaccharide in the end. The physical and chemical behavior of these acetal groups can be adjusted by modifying their stereoelectronic and steric properties, thereby providing materials with tunable degradation and release rates. We have applied this conjugation chemistry in the development of water-soluble siRNA carriers, namely acetal-linked amino-dextrans, with various amine structures attached through either slow- or fast-degrading acetal linker. The carriers with the best combination of amine moieties and structural composition of acetals showed high in vitro transfection efficiency and low cytotoxicity in the delivery of siRNA. © 2012 American Chemical Society.

Citation

Cui, L., Cohen, J. L., Chu, C. K., Wich, P. R., Kierstead, P. H., & Fréchet, J. M. J. (2012). Conjugation Chemistry through Acetals toward a Dextran-Based Delivery System for Controlled Release of siRNA. Journal of the American Chemical Society, 134(38), 15840–15848. doi:10.1021/ja305552u

Acknowledgements

This work was funded through Federal funds from the National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services (contract No. HHSN268201000043C), and the Frechet "various donors" gift fund for the support of research in new materials. P. R. Wich gratefully acknowledges the Alexander von Humboldt Foundation (AvH) for funding. We also thank A. Fischer in the UC Berkeley Cell Culture Facility for her help with cell culture preparation.