Cationic lipid saturation influences intracellular delivery of encapsulated nucleic acids

Heyes, James; Palmer, Lorne; Bremner, K. Helen; MacLachlan, Ian

doi:10.1016/j.jconrel.2005.06.014

Cited by 483 publications

(497 citation statements)

References 28 publications

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“…Proof of concept for LNPfacilitated delivery of self-amplifying RNA vaccines was obtained using a subset of LNPs, called stable nucleic acid lipid particles (SNALPs) (19,27) (Fig. 1B).…”

Section: Resultsmentioning

confidence: 99%

Nonviral delivery of self-amplifying RNA vaccines

Geall

Verma

Otten

et al. 2012

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

568

528

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Despite more than two decades of research and development on nucleic acid vaccines, there is still no commercial product for human use. Taking advantage of the recent innovations in systemic delivery of short interfering RNA (siRNA) using lipid nanoparticles (LNPs), we developed a self-amplifying RNA vaccine. Here we show that nonviral delivery of a 9-kb self-amplifying RNA encapsulated within an LNP substantially increased immunogenicity compared with delivery of unformulated RNA. This unique vaccine technology was found to elicit broad, potent, and protective immune responses, that were comparable to a viral delivery technology, but without the inherent limitations of viral vectors. Given the many positive attributes of nucleic acid vaccines, our results suggest that a comprehensive evaluation of nonviral technologies to deliver self-amplifying RNA vaccines is warranted.vaccine platform | SAM vaccine | respiratory syncytial virus | HIV

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“…Proof of concept for LNPfacilitated delivery of self-amplifying RNA vaccines was obtained using a subset of LNPs, called stable nucleic acid lipid particles (SNALPs) (19,27) (Fig. 1B).…”

Section: Resultsmentioning

confidence: 99%

Nonviral delivery of self-amplifying RNA vaccines

Geall

Verma

Otten

et al. 2012

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

568

528

View full text Add to dashboard Cite

show abstract

“…The low LNP pK a of some formulations can be predicted based on lipid structure. For example, lipid structures with electron-withdrawing groups neighboring the amine in the head group are weak bases (13,20,28,29, and 30) and may thus lead to low LNP pK a 's. Other formulations were less predictable.…”

Section: Discussionmentioning

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).…”

mentioning

confidence: 99%

Multiparametric approach for the evaluation of lipid nanoparticles for siRNA delivery

Alabi

Love

Sahay

et al. 2013

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

149

110

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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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“…It consists of cholesterol, DSPC, D-Lin-DMA and PEG-C-DMA. Among these components, the neutral lipids DSPC and cholesterol are commonly used in many liposome formulations for maintaining liposome structure whereas PEG-C-DMA and DLin-DMA are unique components of SNALP that are critical for its in vivo delivery efficiency (14,15).…”

Section: Introductionmentioning

confidence: 99%

Developing Lipid Nanoparticle-Based siRNA Therapeutics for Hepatocellular Carcinoma Using an Integrated Approach

Wang

Wilcox

et al. 2013

Molecular Cancer Therapeutics

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Successful siRNA therapeutics requires the optimal integration of multiple components, including an efficient delivery system, a disease indication that is appropriate for siRNA-based therapy, and a potent and nontoxic siRNA against a robust therapeutic target. Although all currently available delivery systems have limitations, it is important to recognize that a careful selection of the disease indication, therapeutic target, and siRNA molecule could partially compensate for deficiencies associated with the delivery system and makes it possible to advance a therapeutic siRNA regimen. In this study, we present the development of siRNA therapeutics for hepatocellular carcinoma using an integrated approach, including the development of an efficient lipid nanoparticle delivery system, the identification of a robust therapeutic target that does not trigger liver toxicity upon target knockdown, and the selection of potent and nonimmunogenic siRNA molecules against the target. The resulting siRNA-containing lipid nanoparticles produced significant antitumor efficacy in orthotopic hepatocellular carcinoma models, and, thus, represent a promising starting point for the development of siRNA therapeutics for hepatocellular carcinoma.

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Cationic lipid saturation influences intracellular delivery of encapsulated nucleic acids

Cited by 483 publications

References 28 publications

Nonviral delivery of self-amplifying RNA vaccines

Nonviral delivery of self-amplifying RNA vaccines

Multiparametric approach for the evaluation of lipid nanoparticles for siRNA delivery

Developing Lipid Nanoparticle-Based siRNA Therapeutics for Hepatocellular Carcinoma Using an Integrated Approach

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