Biological Barriers to Therapy with Antisense and siRNA Oligonucleotides

Juliano, Rudolph L.; Bauman, John A.; Kang, Hong Tae; Xin, Ming

doi:10.1021/mp900093r

Cited by 267 publications

(221 citation statements)

References 85 publications

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“…Systemic delivery of naked siRNA to the target tissue is ineffective due to its sensitivity to nuclease degradation and net negative charges which prevents interactions with the plasma membrane [3,4]. Although the emergence of synthetic gene carriers has broadened the potential applications of siRNA therapeutics to a variety of tissue-specific diseases, most carriers have low biocompatability and/or inadequate delivery kinetics.…”

Section: Introductionmentioning

confidence: 99%

Reduction in the size of layered double hydroxide nanoparticles enhances the efficiency of siRNA delivery

Chen

Cooper

Zhou

et al. 2013

Journal of Colloid and Interface Science

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Small interfering RNAs (siRNA) are a potentially powerful new class of pharmaceutical drugs for many diseases, while the delivery of unprotected siRNAs is ineffective due to their susceptibility to degradation by ubiquitous nucleases under physiological conditions. Layered double hydroxide nanoparticles (LDHs) have been found to be efficient carriers of anionic drugs and nucleic acids. Our previous research has shown that LDHs (with the Z-average particle size of approximately 110 nm) can mediate siRNA delivery in mammalian cells, resulting in gene silencing. However, short double-stranded nucleic acids are mostly adsorbed onto the external surface and not well protected by LDHs. In order to enhance the intercalation of siRNA into the LDH interlayer and the efficiency of subsequent siRNA delivery, we prepared smaller LDHs (with the Z-average particle size of approximately 45 nm) with an engineered nonaqueous method. We demonstrate here that dsDNA/siRNA is more effectively intercalated into these small LDH nanoparticles, more dsDNA/siRNA is transfected into HEK 293T cells, and more efficient silencing of the target gene is achieved using smaller LDHs. Thus smaller LDH particles have greater potential as a delivery system for the application of RNA interference.

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Section: Introductionmentioning

confidence: 99%

Reduction in the size of layered double hydroxide nanoparticles enhances the efficiency of siRNA delivery

Chen

Cooper

Zhou

et al. 2013

Journal of Colloid and Interface Science

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“…The short-lived ASO Opn effect in this study may be improved by suited oligonucleotide chemistries such as 2 0 -OH modifications, or the use of locked or peptide nucleic acids. 32,33 In variance to the ASO Opn , its complementary senseoligomer showed an unexpected antitumor effect. The anti-proliferative effect of the SO in vitro was only marginally better, but surpassed that of the ASO Opn significantly in vivo.…”

Section: Discussionmentioning

confidence: 98%

“…General physiological barriers inhibiting a sufficient activity of single-stranded oligomers include a rapid renal clearance, a tight endothelial cell barrier, oligomer degradation by plasma nuclease activity and clearance by immune cells, such as circulating monocytes and tissue macrophages. 32 Several chemical modifications have been developed over the past years for oligomers to deal with these barriers. The most common stabilizing modification against nucleases is the substitution of a sulfur atom for a non-bridging phosphate oxygen atom, as was used for the ASO Opn .…”

Section: Discussionmentioning

confidence: 99%

Influence of osteopontin expression on the metastatic growth of CC531 rat colorectal carcinoma cells in rat liver

et al. 2011

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Development of hepatic metastasis is responsible for most of colorectal cancer-related deaths. Osteopontin (OPN) is a small integrin-binding N-linked glycoprotein, which plays a crucial role in the formation of hepatic metastasis. This study aimed to suppress Opn expression by an antisense-oligonucleotide (ASO Opn ) to decrease liver metastasis in vivo. The effect of ASO Opn was investigated in vitro in CC531 lacZ colorectal cancer cells in comparison to sense (SO) or nonsense (NSO) oligomers, by determining mRNA and protein expression levels, as well as cell survival. For in vivo treatment, CC531 lacZ cells were intraportally inoculated into rats to compare the effects of ASO, SO and NSO oligomers, following prolonged subcutaneous administration by osmotic minipumps. The resulting CC531 lacZ tumor cell load in the liver was measured by a b-galactosidase assay. Proliferation of CC531 lacZ cells in vitro was significantly decreased after ASO Opn and SO treatment (Po0.001). Liver metastasis development was reduced as long as ASO Opn was administered, but this effect was rapidly blunted following the end of the ASO Opn administration. In contrast, administration of the SO resulted in a tumor load reduction, which surprisingly surpassed the ASO Opn effect in vivo in terms of a long-lasting metastasis suppression, which was accompanied with increased survival of the animals. Administration of the ASO Opn in rats was effective in decreasing their liver metastasis. The short-lived effect might be extended by modifications suited to increase the ASOs' half-life. In addition, there was a superior anti-metastatic effect caused by the SO, which has not been reported previously.

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“…This safe consumption results in part from extensive barriers to ingested RNAs, such as low gut pH, nucleases, multiple membrane barriers, and rapid renal elimination of RNA . These barriers are also evidenced by drug delivery challenges faced by developers of oligonucleotide-based drugs (Juliano et al 2009;O'Neill et al 2011;Petrick et al 2013). Further studies in mammals indicate that ingested doublestranded RNAs, even those targeting a gene in the test species, do not produce adverse health effects in these animals (Petrick et al 2015).…”

Section: Jan Verhaert and Jay S Petrick Monsanto Company Belgium Amentioning

confidence: 99%

Advancing the use of noncoding RNA in regulatory toxicology: Report of an ECETOC workshop

Aigner¹,

Buesen²,

Gant³

et al. 2016

Regulatory Toxicology and Pharmacology

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The European Centre for the Ecotoxicology and Toxicology of Chemicals (ECETOC) organised a workshop to discuss the state-of-the-art research on noncoding RNAs (ncRNAs) as biomarkers in regulatory toxicology and as analytical and therapeutic agents. There was agreement that the abundance of data obtained from ncRNA expression profiling requires careful evaluation to determine the utility of specific ncRNAs for regulatory toxicology. To advance the use of ncRNA in regulatory toxicology, the following research priorities were identified: (1) Conduct comprehensive literature reviews to identify candidate ncRNAs for further assessment as potential biomarkers of toxicity and areas of toxicology where ncRNA expression profiling can address prevailing scientific deficiencies.(2) Develop consensus on how to conduct and report ncRNA expression profiling in a toxicological context to support applicability for regulatory decision-making. (3) Conduct experimental projects to evaluate the toxicological relevance of the expression profiles of selected ncRNAs. As necessary, retrospective analyses (e.g. from surplus samples from control groups from regulatory studies) can be supplemented with new (90-day) rat oral toxicity studies. These projects should aim at establishing physiological ncRNA expression profiles including the biological variability of healthy individuals. To substantiate the relevance of key ncRNAs for cell homeostasis or pathogenesis, molecular events should be linked with substance-induced apical effects in a dose-dependent manner. Applying a holistic approach, knowledge on ncRNAs, and relevant information from 'omics and epigenetics technologies, should be integrated into adverse outcome pathways to improve the understanding of the functional roles of ncRNAs within a regulatory context.

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Biological Barriers to Therapy with Antisense and siRNA Oligonucleotides

Cited by 267 publications

References 85 publications

Reduction in the size of layered double hydroxide nanoparticles enhances the efficiency of siRNA delivery

Reduction in the size of layered double hydroxide nanoparticles enhances the efficiency of siRNA delivery

Influence of osteopontin expression on the metastatic growth of CC531 rat colorectal carcinoma cells in rat liver

Advancing the use of noncoding RNA in regulatory toxicology: Report of an ECETOC workshop

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