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Combinatorial synthesis of chemically diverse core-shell nanoparticles for intracellular delivery

Daniel J. Siegwart, Kathryn A. Whitehead, Lutz Nuhn, Gaurav Sahay, Hao Cheng, Shan Jiang, Minglin Ma, Abigail Lytton-Jean, Arturo Vegas, Patrick Fenton, Christopher G. Levins, Kevin T. Love, Haeshin Lee, Christina Cortez, Sean P. Collins, Ying Fei Li, Janice Jang, William Querbes, Christopher Zurenko, Tatiana Novobrantseva, Robert Langer and Daniel G. Anderson
Proceedings of the National Academy of Sciences of the United States of America
Vol. 108, No. 32 (August 9, 2011), pp. 12996-13001
Stable URL: http://www.jstor.org/stable/27979133
Page Count: 6
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Combinatorial synthesis of chemically diverse core-shell nanoparticles for intracellular delivery
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Abstract

Analogous to an assembly line, we employed a modular design for the high-throughput study of 1,536 structurally distinct nanoparticles with cationic cores and variable shells. This enabled elucidation of complexation, internalization, and delivery trends that could only be learned through evaluation of a large library. Using robotic automation, epoxide-functionalized block polymers were combinatorially cross-linked with a diverse library of amines, followed by measurement of molecular weight, diameter, RNA complexation, cellular internalization, and in vitro siRNA and pDNA delivery. Analysis revealed structure-function relationships and beneficial design guidelines, including a higher reactive block weight fraction, stoichiometric equivalence between epoxides and amines, and thin hydrophilic shells. Cross-linkers optimally possessed tertiary dimethylamine or piperazine groups and potential buffering capacity. Covalent cholesterol attachment allowed for transfection in vivo to liver hepatocytes in mice. The ability to tune the chemical nature of the core and shell may afford utility of these materials in additional applications.

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