TY - JOUR
T1 - Combinatorial synthesis of chemically diverse core-shell nanoparticles for intracellular delivery
AU - Siegwart, Daniel J.
AU - Whitehead, Kathryn A.
AU - Nuhn, Lutz
AU - Sahay, Gaurav
AU - Cheng, Hao
AU - Jiang, Shan
AU - Ma, Minglin
AU - Lytton-Jean, Abigail
AU - Vegas, Arturo
AU - Fenton, Patrick
AU - Levins, Christopher G.
AU - Love, Kevin T.
AU - Lee, Haeshin
AU - Cortez, Christina
AU - Collins, Sean P.
AU - Li, Ying Fei
AU - Jang, Janice
AU - Querbes, William
AU - Zurenko, Christopher
AU - Novobrantseva, Tatiana
AU - Langer, Robert
AU - Anderson, Daniel G.
PY - 2011/8/9
Y1 - 2011/8/9
N2 - 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.
AB - 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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U2 - 10.1073/pnas.1106379108
DO - 10.1073/pnas.1106379108
M3 - Article
C2 - 21784981
AN - SCOPUS:80052010600
SN - 0027-8424
VL - 108
SP - 12996
EP - 13001
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 32
ER -