Maximizing the Potency of siRNA Lipid Nanoparticles for Hepatic Gene Silencing In Vivo**

Jayaraman, Muthusamy; Ansell, Steven M.; Mui, Barbara L.; Tam, Ying K.; Chen, Jianxin; Du, Xinyao; Butler, David; Eltepu, Laxman; Matsuda, Shigeo; Narayanannair, Jayaprakash K.; Rajeev, Kallanthottathil G.; Hafez, Ismail; Akinc, Akin; Maier, Martin A.; Tracy, Mark A.; Cullis, Pieter R.; Madden, Thomas D.; Manoharan, Muthiah; Hope, Michael J.

doi:10.1002/anie.201203263

Cited by 929 publications

(876 citation statements)

References 18 publications

Supporting

Mentioning

821

Contrasting

Order By: Relevance

“…These results agree with previous studies that show that the most effective lipid nanoparticles have pKa values in the 5.5-7 range. 3,12,21 Furthermore, the relationships of LNP pKa values with amine head groups (Fig. 5a) and tail groups ( Fig.…”

Section: Lnp Pka Values Influenced Nanoparticle Silencing Efficiencymentioning

confidence: 99%

“…3,12 Several theories have been postulated for entry into the cytoplasm, including the proton sponge effect, diffusion from the endosome to the cytoplasm, leaky endosomes, or electrostatic interactions between ionizable lipids and the negatively charged endosomal membranes. 10,17,27 For lipidoids to be ionized in the early and maturing endosomes for subsequent escape, 25 nanoparticle pKa would need to be in range of 5.5-7.…”

Section: Lnp Pka Values Influenced Nanoparticle Silencing Efficiencymentioning

confidence: 99%

See 1 more Smart Citation

Lipidoid Tail Structure Strongly Influences siRNA Delivery Activity

2016

View full text Add to dashboard Cite

RNA interference therapeutics have been limited, in large part, by the lack of efficient, non-toxic, non-immunogenic delivery systems. Among previously established methods, lipidoid nanoparticles (LNPs) show particular promise in delivering siRNA to diverse cell and organ targets in vitro and in vivo. However, a better understanding of structure-function relationships is needed to facilitate broad translation to clinical applications. Here, we demonstrate the critical role of tail chemistry in conferring delivery efficacy to lipidoid molecules with three or four aliphatic tails. Tail length and structure significantly affected siRNA transfection in HeLa cells, with methacrylate (vs. acrylate) tails and tails containing ethers causing reductions in efficacy. Notably, we report a novel tail precursor, isodecyl acrylate, that conveyed marked siRNA delivery ability in vitro and in vivo. LNPs with isodecyl acrylate lipidoids uniformly induced greater than 90% gene silencing, both in vitro and in mice (hepatocytes), at 40 nM and 0.1 mg/ kg, respectively. Furthermore, we found that tail chemistry significantly influenced the surface pKa values of formulated LNPs, with tails that conferred higher pKa facilitating higher levels of gene knockdown. Together, these data underscore the importance of lipidoid tail structure and provide guidance for the development of next generation lipid nanoparticle siRNA delivery systems.

show abstract

Section: Lnp Pka Values Influenced Nanoparticle Silencing Efficiencymentioning

confidence: 99%

Section: Lnp Pka Values Influenced Nanoparticle Silencing Efficiencymentioning

confidence: 99%

Lipidoid Tail Structure Strongly Influences siRNA Delivery Activity

2016

View full text Add to dashboard Cite

show abstract

“…1,2) Later, a series of ionizable aminolipids were synthesized and utilized for nucleic acid delivery to the liver and to tumors as a formulation of stable nucleic acid-lipid particles (SNALPs) or ionizable lipid nano particles (iLNPs). [3][4][5][6] Recently, we designed a new pH-sensitive cationic lipid, YSK05 (1-methyl-4,4-biz[(9Z,12Z )-octadeca-9,12-dien-1-yloxy]-piperidine). 7) Liposomes containing YSK derivatives with apparent pK a 6.5 were neutral in the blood and positively charged at the early endosome stage, which triggered the release of a cargo into cytosol via membrane fusion, resulting in efficient knockdown in the liver or tumors after systemic administration [8][9][10][11][12] (Fig.…”

Section: Activation In Response To Endogenous/internal Stimulimentioning

confidence: 99%

Recent Advances in Endogenous and Exogenous Stimuli-Responsive Nanocarriers for Drug Delivery and Therapeutics

Hatakeyama

2017

Chem. Pharm. Bull.

View full text Add to dashboard Cite

Significant progress has been achieved in the development of stimuli-responsive nanocarriers for drug delivery, diagnosis, and therapy. Various types of triggers are utilized in the development of nanocarrier delivery. Endogenous factors such as changes in pH, redox, gradient, and enzyme concentration which are linked to disease progression have been utilized for controlling biodistribution and releasing drugs from nanocarriers, as well as increasing subsequent pharmacological activity at the disease site. Nanocarriers which respond to artificially-induced exogenous factors (such as temperature, light, magnetic field, and ultrasound) have also been developed. This review aims to discuss recent advances in the design of stimuliresponsive nanocarriers which appear to have a promising future in medicine.

show abstract

“…In clinical trials, anti-miRs directed against the liver-enriched miR-122 were applied at concentrations between 3 and 7 mg/kg (5 weekly injections), 4 but improved formulations for siRNAs delivery resulted in effective concentrations of <0.01 mg/kg that are required to target liver-expressed genes. 5 If concentrations >10 mg/kg are required to target microRNAs in the cardiovascular system, the therapeutic window may overlap with a dose range, possibly leading to toxic and unspecific effects of delivered RNAs. Safety concerns include hepatotoxic or nephrotoxic effects because ASO including LNA-anti-miRs highly accumulate in these organs.…”

Section: Microrna Therapeuticsmentioning

confidence: 99%

“…5 Additionally, conjugation of ASO to N-acetyl galactosamine (GalNAc, GN3), a high-affinity ligand for the hepatocyte-specific asialoglycoprotein receptor, enhanced the potency by >10-fold compared with unmodified ASO. Similar efforts to augment the uptake to other cells might be possible and would improve the therapeutic usage of anti-miRs in cardiovascular diseases.…”

Section: Circulation Researchmentioning

confidence: 99%