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 (e.g. amine 80, 3-(dimethylamino)-1-propylamine) or piperazine (e.g. amine 227, 3-(4-methyl-1-piperazinyl)propylamine) groups and potential buffering capacity. Covalent cholesterol attachment allowed for transfection in vivo to liver hepatocytes and blood monocyte/macrophage (CD11b+ cells) in mice. The ability to tune the chemical nature of the core and shell may afford utility of these materials in additional applications.

Design of core-shell nanoparticles for efficacious siRNA delivery in vitro and in vivo

243rd National Meeting (2012)

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