Abstract
Lipid nanoparticles (LNP) are the most potent carriers for the delivery of nucleic acid-based therapeutics. The first FDA approved a short interfering RNA (siRNA) drug that uses a cationic LNP system for the delivery of siRNA against human transthyretin (hTTR). However, preparation of such LNP involves tedious multi-step synthesis with relatively low yields. In the present study, we synthesized cationic peptidomimetic functionalized cholesterol (denote Chorn) in straightforward chemical approaches with high yield. When formulated with helper lipids, Chorn LNPs complexed with siRNA to form nanoparticles with an average diameter of 150 nm to 200 nm. Chorn LNP mediated transfection of a green fluorescence protein (GFP) expressing plasmid resulted in 60% GFP positive cells. Moreover, Chorn LNP delivered siRNA against polo-like kinase 1 (Plk1), a disease related gene in cancer cells and efficiently suppressed the expression of the gene, resulting in significant morphological changes in the cell nuclei. Our data suggested that cholesterol based cationic LNP, prepared through a robust chemical strategy, may provide a promising siRNA delivery system.
Highlights
Since the discovery of RNA interference (RNAi) phenomena in Caenorhabditis elegans [1] and the subsequent proof of RNAi in mammalian cells by synthetic short interfering RNA [2], extensive studies have been carried out to potentiate the clinical application of siRNA drugs
We discovered that the configuration of hydrophilic peptidomimetic headgroup of cationic lipids enhances biocompatibility of the resulting lipid nanoparticles (LNP) [21,22]
We coupled ethylenediamine with a more reactive cholesteryl chloroformate to prepare an intermediate 1 with a free amino group (Supporting Information Figure S1), which readily reacted with the carboxyl group of the peptidomimetic when PyBOP was used as a condensing reagent to give Chorn3 (Scheme 1) in an appreciable yield
Summary
Since the discovery of RNA interference (RNAi) phenomena in Caenorhabditis elegans [1] and the subsequent proof of RNAi in mammalian cells by synthetic short interfering RNA (siRNA) [2], extensive studies have been carried out to potentiate the clinical application of siRNA drugs. The reason of such tremendous enthusiasm for development of siRNA drugs is that, unlike small molecular drugs, siRNA drugs can be designed to target any genes at a post-transcriptional level, and the cellular RNA-induced silencing complex (RISC) is so efficient that the IC50 value of siRNA is 100-fold lower than the value of antisense oligonucleotides (ASOs) [3]. Moderate gene transfer efficiency was observed for cationic liposome-mediated delivery of the cystic fibrosis (CF) transmembrane conductance regulator (CFTR)
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