Curiously strong lipidoids

Abstract

Researchers at Alnylam Pharmaceuticals Inc. and the Massachusetts Institute of Technology have developed a class of lipid-like carriers that are nearly 100 times more efficient at delivering small interfering RNA than previously studied lipid-based carriers.1 The parties are now scaling up production of one of the carriers-dubbed lipidoids-and are optimizing it in rodent and nonhuman primate disease models.If successful, lipidoids could address one of the most significant challenges facing RNAi therapeutics: safely and efficiently delivering the molecules to diseased tissue.2 Naked siRNA is the simplest option but has primarily been limited to diseases of the eye, in which direct local delivery is possible. For most other indications, systemic delivery is the only way to go, requiring a carrier to package and protect the molecules from serum nucleases and to selectively target the compounds to the desired tissue.Lipidoids and lipids share many of the physicochemical properties that drive the formation of liposomes for RNAi delivery. However, lipidoids require many fewer steps to synthesize and purify. Those advantages make high throughput combinatorial synthesis of lipidoids and rapid in vitro screening of thousands of potential drug delivery candidates possible.The Alnylam-MIT team previously evaluated a library of more than 1,200 lipidoids, the best of which delivered siRNA in three different animal models: mice, rats and nonhuman primates.3,4 However, the first-generation lipidoids had efficacies that were only comparable to those for existing stable nucleic acid lipid particle formulations, thus requiring siRNA loads in the mg/kg body weight range.The team hoped to improve the therapeutic index and reduce the off-target toxicity of the siRNA loads by lowering dosing to the µg/kg range, and they produced a second-generation library of 126 epoxidederived lipidoids.A cell-based screen of the library identified 12 lipidoids that delivered sufficient siRNA to reduce luciferase gene expression by at least 80% in a transfected cell line. In mouse livers, one of the lipidoids-C12-200-delivered 3, 10 and 30 µg/kg of an siRNA against Factor VII that reduced gene expression by about 25%, 50% and 80%, respectively.Most lipid-based delivery carriers require siRNA doses of at least 1 mg/kg to get more than 50% gene silencing."The lipidoid-siRNA formulation described in the PNAS paper showed an incredibly high efficacy, perhaps two or even three orders of magnitude higher than most previously reported lipid-based RNAi delivery formulations, " said Niren Murthy, associate professor of biomedical engineering at the Georgia Institute of Technology.Given the efficient gene silencing by siRNA delivered with C12-200, the researchers hypothesized that the lipidoid might be able to simultaneously deliver multiple siRNA molecules to the liver without generating toxicity.In mice, a single dose of C12-200 complexed with 0.1 mg/kg of five different siRNAs reduced expression of all five genes by at least 50% compared with C12-200 compl...

Targeting the MAPK pathway in melanoma: Why some approaches succeed and other fail

“…Liposomes protect RNAi from being “detected” by RNAses, and if coupled to specific antibodies or ligands can deliver the particles specifically into melanoma cells. In a recent report researchers at Alnylam Pharmaceuticals Inc. and the Massachusetts Institute of Technology listed ~ 1200 different class of lipid-like barriers called “lipidoids” that are about 100 times more efficient at delivering small interfering RNA than the earlier reported lipid-based barriers [151]. With this technology one can use a loading ranging from 3 to 30μg/kg of siRNA compared to commonly used regular lipid barriers that require at least 1 mg/kg to get more than 50% gene silencing [151].…”

“…In a recent report researchers at Alnylam Pharmaceuticals Inc. and the Massachusetts Institute of Technology listed ~ 1200 different class of lipid-like barriers called “lipidoids” that are about 100 times more efficient at delivering small interfering RNA than the earlier reported lipid-based barriers [151]. With this technology one can use a loading ranging from 3 to 30μg/kg of siRNA compared to commonly used regular lipid barriers that require at least 1 mg/kg to get more than 50% gene silencing [151]. Clinical efficacy of this approach for targeting the MAP kinase pathways remains to be demonstrated [152].…”

Small Players Ruling the Hard Game: siRNA in Bone Regeneration

“…Lipidoids—another class of lipid‐based nanoparticles—have a similar structure to liposomes and are synthesized by conjugating alkyl‐acrylamides and amine molecules. They require fewer steps for fabrication compared to liposomes, which makes them preferential for high‐throughout analysis of different therapeutic agents . Moreover, it has been shown that at a low serum level (2%), the transfection of human umbilical vein endothelial cells (HUVECs) using lipidoid was comparable to Lipofectamine 2000.…”

“…They require fewer steps for fabrication compared to liposomes, which makes them preferential for high-throughout analysis of different therapeutic agents. (96) Moreover, it has been shown that at a low serum level (2%), the transfection of human umbilical vein endothelial cells (HUVECs) using lipidoid was comparable to Lipofectamine 2000. However, at a normal serum level (10%), lipidoids had superior transfection efficiency compared to Lipofectamine 2000.…”

Small non-coding RNAs-based bone regulation and targeting therapeutic strategies

“…Moreover, lipidoids, which possess a similar chemical structure to liposomes, are another new type of lipid-based nanoparticle. Lipidoids gained significantly higher transfection efficiency over Lipofectamine 2000 in human umbilical vein endothelial cells (HUVECs) at a low serum level (2%) (Fulmer, 2010). Ramasubramanian et al performed delivery of BMP-2 DNA along with Noggin and guanine nucleotide binding protein alpha-stimulating activity polypeptide (GNAS) targeting siRNA in an immortalized human foetal osteoblast cell line (hFOB1.19) using a lipidoid called NA114, which was previously reported to be an efficient siRNA carrier (Cho et al, 2009).…”