ABSTRACT
Realizing the full potential of RNAi therapeutics will require the advent of safe and efficient carriers. Since the structure of the ideal vehicle remains unknown, the ability to generate and evaluate many compounds in a high-throughput manner is likely to direct our efforts. One-step conjugation chemistries facilitate the synthesis of large libraries, whose members can be screened for efficacy both in vitro and in vivo. Comparison of the top-performing compounds can yield structure-function relationships that can, in turn, inform the synthesis of iterative libraries. This chapter describes the synthesis, screening, formulation, evolution, and application of “lipidoids”, a novel class of lipid-like molecules that highlights the utility of combinatorial approaches for the production of effective siRNA delivery vehicles.
