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

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

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...

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Bibliographic Details
Main Authors: Whitehead, Kathryn Ann, Nuhn, Lutz, Sahay, Gaurav, Cheng, Hao, Jiang, Shan, Ma, Minglin, Lytton-Jean, Abigail K. R., Vegas, Arturo, Fenton, Patrick, Levins, Christopher G., Lee, Haeshin, Cortez, Christina, Collins, Sean P., Li, Ying Fei, Jang, Janice, Querbes, William, Zurenko, Christopher, Novobrantseva, Tatiana I., Love, Kevin T, Langer, Robert S, Anderson, Daniel Griffith, Siegwart, Daniel J.
Other Authors: Harvard University--MIT Division of Health Sciences and Technology
Format: Article
Language:en_US
Published: National Academy of Sciences (U.S.) 2012
Online Access:http://hdl.handle.net/1721.1/70069
https://orcid.org/0000-0002-2100-1171
https://orcid.org/0000-0002-0100-7824
https://orcid.org/0000-0001-5629-4798
https://orcid.org/0000-0002-3483-5132
https://orcid.org/0000-0001-9522-8208
https://orcid.org/0000-0003-4255-0492
Description
Summary: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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