A Bifurcated Proteoglycan Binding Small Molecule Carrier for si<scp>RNA</scp> Delivery

Gooding, Matt; Adigbli, Derick; Chan, A. W. Edith; Melander, Roberta J.; MacRobert, Alexander J.; Selwood, David L.

doi:10.1111/cbdd.12295

Cited by 14 publications

(14 citation statements)

References 31 publications

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“…Another interesting study, primarily germane to muscle tissue, found that the clinically utilized drug dantrolene improved the effects of SSOs that correct dystrophin expression in a model of Duchennne muscular dystrophy [148]; however the precise mechanism of action is unclear. Yet another study demonstrated increased delivery of siRNA using guanidine-like small molecules that complex with the siRNA and that may also bind to cell surface proteoglycans to improve cell uptake [149]. A recent conference proceeding [150] described a small molecule, Guanabenz, that also complexed with siRNA and enhanced uptake and effects in cell culture.…”

Section: Endocytosis and Trafficking Of Oligonucleotidesmentioning

confidence: 99%

Cellular uptake and intracellular trafficking of oligonucleotides

Juliano

Carver

2015

Advanced Drug Delivery Reviews

118

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Oligonucleotides manifest much promise as potential therapeutic agents. However, understanding of how oligonucleotides function within living organisms is still rather limited. A major concern in this regard is the mechanisms of cellular uptake and intracellular trafficking of both ‘free’ oligonucleotides and oligonucleotides associated with various polymeric or nanocarrier delivery systems. Here we review basic aspects of the mechanisms of endocytosis and intracellular trafficking and how insights from these processes can be used to understand oligonucleotide delivery. In particular we discuss opportunities for escape of oligonucleotides from endomembrane compartments and describe recent studies using small molecules to enhance oligonucleotide effects.

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Section: Endocytosis and Trafficking Of Oligonucleotidesmentioning

confidence: 99%

Cellular uptake and intracellular trafficking of oligonucleotides

Juliano

Carver

2015

Advanced Drug Delivery Reviews

118

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“…Stable plasma membrane association could be a result of hsiRNA charge shielding via a non-covalent RNA-Guanabenz interaction. Indeed, the highly basic guanidinium moiety is analogous to an arginine side-chain, a feature commonly observed in cationic cell-penetrating peptides such as the HIV-derived TAT peptide or the non-viral penetratin ( 16 , 22 ). The observed impact on the level of hsiRNA cellular association is specific to early time points, as overall level of internalized oligonucleotides equilibrates by 24 h with no significant alteration in co-localization with lysosomal markers (Figure 3B ).…”

Section: Resultsmentioning

confidence: 99%

“…First, Gooding et al . have reported the synthesis of small molecule carriers (SMoC) of siRNA, which form non-covalent electrostatic interactions with unmodified siRNA to enhance plasma membrane translocation ( 16 , 17 ). Second, Juliano's group demonstrated that the small molecule Retro-1, which is involved in retrograde transport of bacterial toxins, appreciably improved the activity of nuclear-localized ASOs following simultaneous transfection.…”

Section: Introductionmentioning

confidence: 99%

Guanabenz (Wytensin™) selectively enhances uptake and efficacy of hydrophobically modified siRNAs

et al. 2015

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One of the major obstacles to the pharmaceutical success of oligonucleotide therapeutics (ONTs) is efficient delivery from the point of injection to the intracellular setting where functional gene silencing occurs. In particular, a significant fraction of internalized ONTs are nonproductively sequestered in endo-lysosomal compartments. Here, we describe a two-step, robust assay for high-throughput de novo detection of small bioactive molecules that enhance cellular uptake, endosomal escape, and efficacy of ONTs. Using this assay, we screened the LOPAC (Sigma–Aldrich) Library of Pharmacologically Active Compounds and discovered that Guanabenz acetate (Wytensin™), an FDA-approved drug formerly used as an antihypertensive agent, is capable of markedly increasing the cellular internalization and target mRNA silencing of hydrophobically modified siRNAs (hsiRNAs), yielding a ∼100-fold decrease in hsiRNA IC50 (from 132 nM to 2.4 nM). This is one of the first descriptions of a high-throughput small-molecule screen to identify novel chemistries that specifically enhance siRNA intracellular efficacy, and can be applied toward expansion of the chemical diversity of ONTs.

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“…The authors hypothesised that in the presence of lipid membranes, the carrier structure was able to unfold allowing the hydrophobic porphyrin to be inserted into the lipid membrane. PCI could similarly be applied to the delivery of small molecule carrier systems (SMoC) in the delivery of siRNA or miRNA …”

Section: Cytotoxic Agents Used With Pcimentioning

confidence: 99%

“…PCI could similarly be applied to the delivery of small molecule carrier systems (SMoC) in the delivery of siRNA or miRNA. 57…”

Section: Macromolecular Drug Carriersmentioning

confidence: 99%

Enhancing the efficacy of cytotoxic agents for cancer therapy using photochemical internalisation

Bayona

Moore

Loizidou

et al. 2015

Intl Journal of Cancer

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Photochemical internalisation (PCI) is a technique for improving cellular delivery of certain bioactive agents which are prone to sequestration within endolysosomes. There is a wide range of agents suitable for PCI‐based delivery including toxins, oligonucleotides, genes and immunoconjugates which demonstrates the versatility of this technique. The basic mechanism of PCI involves triggering release of the agent from endolysosomes within the target cells using a photosensitiser which is selectively retained with the endolysosomal membranes. Excitation of the photosensitiser by visible light leads to disruption of the membranes via photooxidative damage thereby releasing the agent into the cytosol. This treatment enables the drugs to reach their intended subcellular target more efficiently and improves their efficacy. In this review we summarise the applications of this technique with the main emphasis placed on cancer chemotherapy.

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A Bifurcated Proteoglycan Binding Small Molecule Carrier for siRNA Delivery

Cited by 14 publications

References 31 publications

Cellular uptake and intracellular trafficking of oligonucleotides

Cellular uptake and intracellular trafficking of oligonucleotides

Guanabenz (Wytensin™) selectively enhances uptake and efficacy of hydrophobically modified siRNAs

Enhancing the efficacy of cytotoxic agents for cancer therapy using photochemical internalisation

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