Biodegradable lipid nanoparticles induce a prolonged RNA interference-mediated protein knockdown and show rapid hepatic clearance in mice and nonhuman primates

Suzuki, Yuta; Hyôdô, Kenji; Suzuki, Takuya; Tanaka, Yohei; Kikuchi, Hiroshi; Ishiguro, Hiroshi

doi:10.1016/j.ijpharm.2017.01.016

Cited by 50 publications

(47 citation statements)

References 31 publications

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“…Furthermore, we showed a slight increase, but not significant, of AST level in mice treated with miR-634 -LNPs compared with mice treated with miR-NC -LNPs, suggesting that this change may be attributed by an enforced miR-634 expression in livers. L101, the next generation of L021, was recently developed and shown to be rapidly cleared by metabolic degradation in the liver 16 . Thus, biodegradable LNPs, coupled with a decreased LNP dosage, will be crucial for improving hepatotoxicity and obtaining a high therapeutic index without causing adverse events.…”

Section: Discussionmentioning

confidence: 99%

“…LNPs harboring ds- miR-NC or ds- miR-634 were formulated using L021, an ionizable lipid with an asymmetric lipid tail, according to a previously reported procedure 15 , 16 . The miRNAs were dissolved in 10 mM citric acid buffer (pH 4.0).…”

Section: Methodsmentioning

confidence: 99%

“…In the present study, we formulated lipid nanoparticles (LNPs) 15 , 16 incorporating ds- miR-634 mimics. Intravenously administered miR-634- LNP effectively delivered ds- miR-634 mimics to tumors in BxPC-3 tumor-bearing mice.…”

Section: Introductionmentioning

confidence: 99%

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Therapeutic Potential of LNP-Mediated Delivery of miR-634 for Cancer Therapy

Gokita

Inoue

Ishiguro

et al. 2020

Molecular Therapy - Nucleic Acids

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MicroRNAs (miRNAs) are endogenous small noncoding RNAs that negatively regulate gene expression by interfering with the translation or stability of target transcripts. Some tumor-suppressive miRNAs can concurrently target multiple cancer-promoting genes and may be useful as therapeutic anticancer agents. However, the development of drug delivery systems is critical for the implementation of miRNA-based therapeutics. We have previously demonstrated that the enforced expression of miR-634 effectively induces apoptosis by concurrently and directly targeting genes associated with mitochondrial homeostasis, antiapoptosis signaling, antioxidant ability, and autophagy in cancer cells. In the current study, we validated the therapeutic potential of lipid nanoparticle (LNP)-mediated delivery of miR-634 for cancer therapy. We confirmed the ability of enforced expression of miR-634 to induce apoptosis in various cancer cell lines, including pancreatic cancer cells. Intravenous administration of LNPs harboring miR-634 significantly reduced the xenograft tumor growth of BxPC-3 pancreatic cancer cells in mice. These findings suggest that LNP-mediated delivery of miR-634 can potentially be used for cancer therapy.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Therapeutic Potential of LNP-Mediated Delivery of miR-634 for Cancer Therapy

Gokita

Inoue

Ishiguro

et al. 2020

Molecular Therapy - Nucleic Acids

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“…PCSK9-targeted siRNA LNPs displayed high efficacy with more than 90% protein silencing following IV administration in non-human primates. This particular formulation also showed higher hepatic clearance and therefore exhibited a superior safety profile [ 56 ].…”

Section: Lipid-based Vectorsmentioning

confidence: 99%

Role of Lipid-Based and Polymer-Based Non-Viral Vectors in Nucleic Acid Delivery for Next-Generation Gene Therapy

et al. 2020

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The field of gene therapy has experienced an insurgence of attention for its widespread ability to regulate gene expression by targeting genomic DNA, messenger RNA, microRNA, and short-interfering RNA for treating malignant and non-malignant disorders. Numerous nucleic acid analogs have been developed to target coding or non-coding sequences of the human genome for gene regulation. However, broader clinical applications of nucleic acid analogs have been limited due to their poor cell or organ-specific delivery. To resolve these issues, non-viral vectors based on nanoparticles, liposomes, and polyplexes have been developed to date. This review is centered on non-viral vectors mainly comprising of cationic lipids and polymers for nucleic acid-based delivery for numerous gene therapy-based applications.

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“…Attempts have been made to avoid or minimize such cationic lipid-mediated cytotoxicity. These include the introduction of biodegradable linkages, including an ester bond, into the structure of the cationic lipids, which leads to their rapid elimination after delivery of the cargo [14][15][16]. Maier et al reported that biodegradable cationic lipids are rapidly degraded and eliminated from the animal body, and showed a higher degree of safety compared to a counterpart with low biodegradability.…”

Section: Introductionmentioning

confidence: 99%

Neutralization of negative charges of siRNA results in improved safety and efficient gene silencing activity of lipid nanoparticles loaded with high levels of siRNA

Sato

Matsui

Sato

et al. 2018

Journal of Controlled Release

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Lipid nanoparticles (LNPs) are one of the leading technologies for the in vivo delivery of short interfering RNA (siRNA). Cationic lipids are an important component for efficient endosomal escape via membrane fusion followed by release of siRNAs in cytosol where the site of action is located. A high cationic lipid/siRNA charge ratio is usually necessary for maximizing the gene silencing activity of the siRNA-loaded LNPs. However, high levels of cationic lipids are known to cause cytotoxicity through interactions with negatively charged biocomponents. A strategy for solving this dilemma is important, in terms of producing clinically applicable LNPs with a wide therapeutic window. We herein report on the development of LNPs with a high gene silencing activity and a low cationic lipid/siRNA charge ratio, which we refer to as low lipid core-nanoparticles (LLC-NPs). The negative charges of the siRNAs were neutralized by protamines, cationic proteins, to reduce the net dose of cationic lipid, YSK05, which was developed in our laboratory, for endosomal escape, resulting in preserved fusogenic activity and gene silencing activity, both in vitro and in vivo factor VII mouse model. In addition, the LLC-NPs showed an improved hepatotoxicity compared to conventional LNPs, which have a relatively higher cationic lipid/siRNA charge ratio. The concept of the LLC-NPs helps to realize clinically applicable LNPs with a wide therapeutic window and has the potential for use in various applications and for the delivery of different classes of nucleic acid.

show abstract

Biodegradable lipid nanoparticles induce a prolonged RNA interference-mediated protein knockdown and show rapid hepatic clearance in mice and nonhuman primates

Cited by 50 publications

References 31 publications

Therapeutic Potential of LNP-Mediated Delivery of miR-634 for Cancer Therapy

Therapeutic Potential of LNP-Mediated Delivery of miR-634 for Cancer Therapy

Role of Lipid-Based and Polymer-Based Non-Viral Vectors in Nucleic Acid Delivery for Next-Generation Gene Therapy

Neutralization of negative charges of siRNA results in improved safety and efficient gene silencing activity of lipid nanoparticles loaded with high levels of siRNA

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