A combinatorial library of lipid-like materials for delivery of RNAi therapeutics

Abstract

The safe and effective delivery of RNA interference (RNAi) therapeutics remains an important challenge for clinical development. The diversity of current delivery materials remains limited, in part because of their slow, multi-step syntheses. Here we describe a new class of lipid-like delivery molecules, termed lipidoids, as delivery agents for RNAi therapeutics. Chemical methods were developed to allow the rapid synthesis of a large library of over 1,200 structurally diverse lipidoids. From this library, we identified lipidoids that facilitate high levels of specific silencing of endogenous gene transcripts when formulated with either double-stranded small interfering RNA (siRNA) or single-stranded antisense 2'-O-methyl (2'-OMe) oligoribonucleotides targeting microRNA (miRNA). The safety and efficacy of lipidoids were evaluated in three animal models: mice, rats and nonhuman primates. The studies reported here suggest that these materials may have broad utility for both local and systemic delivery of RNA therapeutics.

Hybrid pulmonary surfactant-coated nanogels mediate efficient in vivo delivery of siRNA to murine alveolar macrophages

“…Moreover, promising results were obtained upon inhalation of free siRNA in human clinical trials for the treatment of patients infected with respiratory syncytial virus [36]. However, recent publications have clearly demonstrated the benefit of nanocarriers for siRNA inhalation therapy [9,32,37]. This was confirmed by our work, as the aspiration of free siRNA in the bronchoalveolar lumen of BALB/c mice resulted in negligible siRNA internalization by rAM and hence also failed to elicit a gene silencing effect.…”

“…This can possibly be attributed to the adsorption of negatively charged components from the endogenous alveolar surfactant onto the surface of the uncoated siNGs, as already illustrated in the literature for other types of nanoparticles [30,31]. The cd 45 gene was selected as a model target gene to assess the RNAi effect [32]. Strikingly, despite the high intracellular siRNA doses in rAM obtained with both uncoated and surfactant-coated siNGs, only the latter were able to induce a significant CD45 knockdown in rAM.…”

Special delivery: targeted therapy with small RNAs

“…Although no immune response was reported, small increases in serum levels of two liver enzymes and a reduction in platelet count suggests a potential concern about liver toxicity. 35,36 Further design modifications of liposomes may improve the therapeutic index by enhancing intracellular delivery and/or further reducing cytotoxicity and immune stimulation.…”

Cancer Stem Cells: Formidable Allies of Cancer

“…Depending on their role as pro-tumorigenic or anti-tumorigenic, they can be down-regulated or over-expressed, respectively. Down-regulation is achieved using anti-miRNA oligonucleotides (AMOs) or their modifications [125][126][127], miRNA sponges [128] or miR-masking, whereas overexpression can be achieved using liposomal delivery systems [129] and synthetic miRNA mimics [130].…”