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.

Hairy nanoparticle assemblies as one-component functional polymer nanocomposites: opportunities and challenges

“…HNPs; first creating BCP micelles [110] or stars, [113] and then crosslinking the inner block to form the rigid particle.…”

Modular degradable dendrimers enable small RNAs to extend survival in an aggressive liver cancer model

“…S ince the discovery of RNAi and the recognition of its therapeutic potential, there has been a continuous search for optimal delivery carriers (1)(2)(3)(4)(5)(6)(7)(8)(9)(10). Tremendous progress has been made with regard to delivery efficacy of small RNAs to healthy livers, but the clinically required combination of high delivery potency to tumors and low hepatotoxicity is not currently met by existing delivery vehicles.…”

“…Studies of lipid and polymer carriers have implicated at least two common elements: chemical groups to bind small RNAs and nanoparticle (NP)-stabilizing hydrophobicity, which combine to encapsulate RNA molecules inside stable NPs and release small RNAs into the cytosol after endocytosis (35). Particular tertiary amines with optimal pK a , alkyl chains, and defined topology/ structure have been identified in effective carriers (2)(3)(4)(5)(6)(7)(8)(9)(10)(35)(36)(37).…”

A fluorinated dendrimer achieves excellent gene transfection efficacy at extremely low nitrogen to phosphorus ratios

“…C ationic polymers are widely used as promising gene vectors to introduce exogenous nucleic acid into cells [1][2][3][4][5][6][7] . These materials are easy-to-manufacture and have superior safety compared with viral gene vectors; however, their commercial and clinical applications are limited by relatively low transfection efficacy and poor cell viability after transfection [8][9][10][11] .…”