title: Combinatorial synthesis of chemically diverse core-shell nanoparticles for intracellular delivery.
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.
authors.affiliation: David H Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Siegwart
authors.forename: Kathryn A
authors.initials: KA
authors.lastname: Whitehead
authors.forename: Lutz
authors.initials: L
authors.lastname: Nuhn
authors.forename: Gaurav
authors.initials: G
authors.lastname: Sahay
authors.forename: Hao
authors.initials: H
authors.lastname: Cheng
authors.forename: Shan
authors.initials: S
authors.lastname: Jiang
authors.forename: Minglin
authors.initials: M
authors.lastname: Ma
authors.forename: Abigail
authors.initials: A
authors.lastname: Lytton-Jean
authors.forename: Arturo
authors.initials: A
authors.lastname: Vegas
authors.forename: Patrick
authors.initials: P
authors.lastname: Fenton
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Levins
authors.forename: Kevin T
authors.initials: KT
authors.lastname: Love
authors.forename: Haeshin
authors.initials: H
authors.lastname: Lee
authors.forename: Christina
authors.initials: C
authors.lastname: Cortez
authors.forename: Sean P
authors.initials: SP
authors.lastname: Collins
authors.forename: Ying Fei
authors.initials: YF
authors.lastname: Li
authors.forename: Janice
authors.initials: J
authors.lastname: Jang
authors.forename: William
authors.initials: W
authors.lastname: Querbes
authors.forename: Christopher
authors.initials: C
authors.lastname: Zurenko
authors.forename: Tatiana
authors.initials: T
authors.lastname: Novobrantseva
authors.forename: Robert
authors.initials: R
authors.lastname: Langer
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Anderson
mesh_terms: D000818:Animals; D020650:Combinatorial Chemistry Techniques / Q000379:methods*; D005167:Factor VII / Q000378:metabolism; D020868:Gene Silencing; D018014:Gene Transfer Techniques; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism; D042541:Intracellular Space / Q000378:metabolism*; D008099:Liver / Q000166:cytology; D051379:Mice; D053758:Nanoparticles / Q000737:chemistry*; D034741:RNA, Small Interfering / Q000378:metabolism
chemical_list: D034741:RNA, Small Interfering; D005167:Factor VII