Evaluation of Efficacy, Biodistribution, and Inflammation for a Potent siRNA Nanoparticle: Effect of Dexamethasone Co-treatment

Abstract

Despite recent progress, systemic delivery remains the major hurdle for development of safe and effective small inhibitory RNA (siRNA)-based therapeutics. Encapsulation of siRNA into liposomes is a promising option to overcome obstacles such as low stability in serum and inefficient internalization by target cells. However, a major liability of liposomes is the potential to induce an acute inflammatory response, thereby increasing the risk of numerous adverse effects. In this study, we characterized a liposomal siRNA delivery vehicle, LNP201, which is capable of silencing an mRNA target in mouse liver by over 80%. The biodistribution profile, efficacy after single and multiple doses, mechanism of action, and inflammatory toxicity are characterized for LNP201. Furthermore, we demonstrate that the glucocorticoid receptor (GR) agonist dexamethasone (Dex) inhibits LNP201-induced cytokine release, inflammatory gene induction, and mitogen-activated protein kinase (MAPK) phosphorylation in multiple tissues. These data present a possible clinical strategy for increasing the safety profile of siRNA-based drugs while maintaining the potency of gene silencing.

Intratumor RNA interference of cell cycle genes slows down tumor progression

“…Here, we have tested an LNP formulation, LNP201, originally designed for liver transduction 16 with the objective of delivering siRNAs targeting the cell cycle genes, KSP and PLK1. KSP is currently the target of intense research for the development of novel anticancer therapeutics.…”

“…LNP201 encapsulating siRNAs were synthesized by Sirna (San Francisco, CA, USA) as described in Abrams et al 16 The LNPs used in this study have a size o150 nm, contain diffusible 1-[8¢-(1,2-dimyristoyl-3-propanoxy)-carboxamido-3¢, 6¢-dioxaoctanyl]carbam-oyl-methyl-poly(ethylene glycol) (PEG-DMG; designed for liver uptake) and the following composition: 50.3% Clin-DMA, 44.3% cholesterol, 5.4% 1-[8¢-(1,2-dimyristoyl-3-propanoxy)-carboxamido-3¢,6¢-dioxaoctanyl]carbam-oyl-methyl-poly(ethylene glycol). siRNA targeting firefly luciferase (luc) was used to demonstrate in vitro and in vivo knockdown activity.…”

“…15 In particular, a liposomal RNA delivery vehicle, LNP201, has been recently developed and shown to cause sustained silencing of target genes in the mouse liver. 16 Similarly, viral vectors are particularly attractive because they can induce long-term knockdown of gene transcripts in vivo. 17 Therefore, the use of RNAi by a stable viral vector system, such as the adenovirus (Ad), is a possible strategy for stable gene knockdown.…”

Quantitative evaluation of siRNA delivery in vivo

“…It, however, fails to examine steps beyond organ uptake such as cellular internalization and endosome escape, which are important for siRNA delivery. Because of this, the total siRNA in tissues does not always correlate with efficacy (Abrams et al 2010). Imaging analysis may yield relevant information on subcellular siRNA delivery, but it is not always precise in quantification and it cannot distinguish between intact siRNA and the free labels released from siRNA by metabolism (Morin et al 2009).…”

Systemic delivery of E6/7 siRNA using novel lipidic particles and its application with cisplatin in cervical cancer mouse models

“…Although this is encouraging, it must be noted that the application site of this cationic delivery system would be restricted to first-pass organs, such as lungs or liver. [23][24][25][26] Its application for treatment of tumours located elsewhere in the body would, thus, be limited unless extremely high doses were used, as is the case for the studies performed using cationic cardiolipin-based liposomes in subcutaneous breast or prostate cancer mouse models (15 mg kg À1 per day for 5 days). 27,28 This, along with the possibility of embolism occurring after administration, would be likely to limit their clinical applications.…”