Lipid-like materials for low-dose, in vivo gene silencing

Love, Kevin T.; Mahon, Kerry P.; Levins, Christopher G.; Whitehead, Kathryn A.; Querbes, William; Dorkin, J. Robert; Qin, June; Cantley, William; Qin, Liu Liang; Racie, Timothy; Frank-Kamenetsky, Maria; Yip, Ka Ning; Alvarez, Rene; Sah, Dinah W.Y.; Fougerolles, Antonin de; Fitzgerald, Kevin; Koteliansky, Victor; Akinc, Akin; Langer, Robert; Anderson, Daniel G.

doi:10.1073/pnas.0910603106

Cited by 835 publications

(830 citation statements)

References 34 publications

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“…To generate meaningful relationships between structure, biological function, and biological activity, we created a diverse set of lipids for formulation with siRNAs into LNPs. Recent high-throughput screens of lipidlike materials indicate that structures with multiple short alkyl tails stemming from a polyamine core are able to facilitate efficient gene silencing (22,23). To synthesize pure multitailed structures with varying polyamine head-group architectures, we designed a rapid and efficient two-step solvent-free synthetic route that requires neither protection/deprotection steps nor the use of costly and time-consuming chromatographic purification.…”

Section: Resultsmentioning

confidence: 99%

“…To address some of these challenges, single-parameter studies that evaluate the effect of chemical structure on a single biological property or on delivery performance have been carried out (16)(17)(18)(19)(20)(21). Furthermore, high-throughput synthetic methods have been exploited for the accelerated discovery of potent lipid nanoparticles (LNP) and evaluation of structure activity relationships (SAR) (22,23). Despite these efforts, the relationships between physicochemical properties of nanoparticles and biological barriers, and that between biological barriers and genesilencing activity remain unclear.…”

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confidence: 99%

“…LNPs were used in this study because they have been shown to facilitate efficient delivery to hepatic and immune targets (23,(25)(26)(27). In the past few years, LNPs formulated with siRNAs against transthyretin (TTR) and proprotein convertase subtilisin/kexin type 9 (PCSK9) in rodents and nonhuman primates have produced promising preclinical results and several clinical trials involving LNPs are currently underway (28)(29)(30).…”

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confidence: 99%

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Multiparametric approach for the evaluation of lipid nanoparticles for siRNA delivery

Alabi

Love

Sahay

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Nanoparticle-mediated siRNA delivery is a complex process that requires transport across numerous extracellular and intracellular barriers. As such, the development of nanoparticles for efficient delivery would benefit from an understanding of how parameters associated with these barriers relate to the physicochemical properties of nanoparticles. Here, we use a multiparametric approach for the evaluation of lipid nanoparticles (LNPs) to identify relationships between structure, biological function, and biological activity. Our results indicate that evaluation of multiple parameters associated with barriers to delivery such as siRNA entrapment, pK a , LNP stability, and cell uptake as a collective may serve as a useful prescreening tool for the advancement of LNPs in vivo. This multiparametric approach complements the use of in vitro efficacy results alone for prescreening and improves in vitro-in vivo translation by minimizing false negatives. For the LNPs used in this work, the evaluation of multiple parameters enabled the identification of LNP pK a as one of the key determinants of LNP function and activity both in vitro and in vivo. It is anticipated that this type of analysis can aid in the identification of meaningful structure-functionactivity relationships, improve the in vitro screening process of nanoparticles before in vivo use, and facilitate the future design of potent nanocarriers.RNAi | thiol-yne | gene silencing | drug carrier

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Section: Resultsmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Multiparametric approach for the evaluation of lipid nanoparticles for siRNA delivery

Alabi

Love

Sahay

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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149

110

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“…An ionizable cationic lipid called DLinKC2DMA, which was originally shown to deliver siRNA to liver cells (26), was also reported to deliver siRNA to mouse macrophages and DCs (27). Similarly, a lipidoid nanoparticle called C12-200, also developed originally for liver-specific siRNA delivery (28), was recently shown to target monocytes, and silencing CCR2 with this reagent was shown to reduce a number of inflammatory conditions in mice (18). siRNAs synthetically linked to C-phosphate-G (CpG) oligonucleotide has also been used to deliver siRNA to toll-like receptor (TLR)-9 + murine macrophages and B cells (29).…”

Section: Discussionmentioning

confidence: 99%

Human macrophage and dendritic cell-specific silencing of high-mobility group protein B1 ameliorates sepsis in a humanized mouse model

Choi

Abraham

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Hypersecretion of cytokines by innate immune cells is thought to initiate multiple organ failure in murine models of sepsis. Whether human cytokine storm also plays a similar role is not clear. Here, we show that human hematopoietic cells are required to induce sepsisinduced mortality following cecal ligation and puncture (CLP) in the severely immunodeficient nonobese diabetic (NOD)/SCID/IL2Rγ −/− mice, and siRNA treatment to inhibit HMGB1 release by human macrophages and dendritic cells dramatically reduces sepsis-induced mortality. Following CLP, compared with immunocompetent WT mice, NOD/SCID/IL2Rγ −/− mice did not show high levels of serum HMGB1 or murine proinflammatory cytokines and were relatively resistant to sepsis-induced mortality. In contrast, NOD/SCID/IL2Rγ −/− mice transplanted with human hematopoietic stem cells [humanized bone marrow liver thymic mice (BLT) mice] showed high serum levels of HMGB1, as well as multiple human but not murine proinflammatory cytokines, and died uniformly, suggesting human cytokines are sufficient to induce organ failure in this model. Moreover, targeted delivery of HMGB1 siRNA to human macrophages and dendritic cells using a short acetylcholine receptor (AchR)-binding peptide [rabies virus glycoprotein (RVG)-9R] effectively suppressed secretion of HMGB1, reduced the human cytokine storm, human lymphocyte apoptosis, and rescued humanized mice from CLP-induced mortality. siRNA treatment was also effective when started after the appearance of sepsis symptoms. These results show that CLP in humanized mice provides a model to study human sepsis, HMGB1 siRNA might provide a treatment strategy for human sepsis, and RVG-9R provides a tool to deliver siRNA to human macrophages and dendritic cells that could potentially be used to suppress a variety of human inflammatory diseases.

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“…Because of these virtues associated with pH-sensitive carriers, several groups have reported on some original pH sensitive systems [29][30][31][32]. To date, one of the most effective systems is lipid nano particles (LNPs), which consist of a hydrophilic moiety containing a tertiary amino group, a linker and two hydrophobic dialkene groups [33].…”

Section: Sirna Delivery To Tumors and The Tumor Vasculature Using A Pmentioning

confidence: 99%

“Programmed packaging” for gene delivery

Hyodo

Sakurai

Akita

et al. 2014

Journal of Controlled Release

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We report on the development of a Multifunctional Envelope-type Nano Device (MEND) based on our packaging concept "Programmed Packaging" to control not only intracellular trafficking but also the biodistribution of encapsulated compounds such as nucleic acids/proteins/peptides. Our strategy for achieving this is based on molecular mechanisms of cell biology such as endocytosis, vesicular trafficking, etc. In this review, we summarize the concept of programmed packaging and discuss some of our recent successful examples of using MENDs. Systematic evolution of ligands by exponential enrichment (SELEX) was applied as a new methodology for identifying a new ligand toward cell or mitochondria. The delivery of siRNA to tumors and the tumor vasculature was achieved using pH sensitive lipid (YSK05), which was newly designed and optimized under in vivo conditions. The efficient delivery of pDNA to immune cells such as dendritic cells has also been developed using the KALA ligand, which can be a breakthrough technology for DNA vaccine. Finally, ss-cleavable and pH-activated lipid-like surfactant (ssPalm) which is a lipid like material with pH-activatable and SS-cleavable properties is also introduced as a proof of our concept.

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Lipid-like materials for low-dose, in vivo gene silencing

Cited by 835 publications

References 34 publications

Multiparametric approach for the evaluation of lipid nanoparticles for siRNA delivery

Multiparametric approach for the evaluation of lipid nanoparticles for siRNA delivery

Human macrophage and dendritic cell-specific silencing of high-mobility group protein B1 ameliorates sepsis in a humanized mouse model

“Programmed packaging” for gene delivery

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