Characterisation of cationic amphiphilic cyclodextrins for neuronal delivery of siRNA: Effect of reversing primary and secondary face modifications

O’Mahony, Aoife; Doyle, David J.; Darcy, Raphael; Cryan, John F.; O’Driscoll, Caitriona M.

doi:10.1016/j.ejps.2012.08.020

Cited by 25 publications

(10 citation statements)

References 36 publications

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“…The variations observed in knockdown efficiency using this particular SC12CDClick-propylamine are likely due to the different microenvironments within each cell type and target gene examined. A variety of knockdown levels have also been reported in other studies using several different modified CD constructs, ranging from *40% to 80% (33,(51)(52)(53) using both in vitro and in vivo models.…”

Section: Discussionmentioning

confidence: 86%

“…Analysis of SC12CDClickpropylamine-siRNA nanocomplexes in this current study and previous studies has shown that they are capable of forming compact nanocomplexes between 125 and 200 nm in size and are highly cationic in nature using dH 2 O. (16,17,33,34) In addition, previous gel Table 3. SC12CDClickpropylamine-siRNA Nanocomplex Droplet Sizes Generated electrophoresis analysis by our group has also demonstrated that SC12CDClickpropylamine nanocomplexes efficiently encapsulate siRNA at MR > 10.…”

Section: Discussionmentioning

confidence: 99%

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Early-Stage Development of Novel Cyclodextrin-siRNA Nanocomplexes Allows for Successful Postnebulization Transfection of Bronchial Epithelial Cells

Hibbitts

O’Mahony²,

Forde³

et al. 2014

Journal of Aerosol Medicine and Pulmonary Drug Delivery

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Background: Successful delivery of small interfering RNA (siRNA) to the lungs remains hampered by poor intracellular delivery, vector-mediated cytotoxicity, and an inability to withstand nebulization. Recently, a novel, cyclodextrin (CD), SC12CDClickpropylamine, consisting of distinct lipophilic and cationic subunits, has been shown to transfect a number of cell types. However, the suitability of this vector for pulmonary siRNA delivery has not been assessed to date. To address this, a series of high-content analysis (HCA) and postnebulization assays were devised to determine the potential for CD-siRNA delivery to the lungs. Methods: SC12CDClickpropylamine-siRNA mass ratios (MRs) were examined for size and zeta potential. Indepth analysis of nanocomplex uptake and toxicity in Calu-3 bronchial epithelial cells was examined using IN Cell Ò HCA assays. Nebulized SC12CDClickpropylamine nanocomplexes were assessed for volumetric median diameter (VMD) and fine particle fraction (FPF) and compared with saline controls. Finally, postnebulization stability was determined by comparing luciferase knockdown elicited by SC12CDClickpropylamine nanocomplexes before and after nebulization. Results: SC12CDClickpropylamine-siRNA complexation formed cationic nanocomplexes of £ 200 nm in size and led to significantly higher levels of siRNA uptake into Calu-3 cells compared with RNAiFect-siRNAtreated cells at all MRs ( p < 0.001, n¼3 · 4), with evidence of toxicity only at MRs 50-100. Nebulization of SC12CDClickpropylamine nanocomplexes using the Aeroneb Ò Pro resulted in VMDs of *5 lm and FPFs of *57% at all MRs. SC12CDClickpropylamine-siRNA-mediated luciferase knockdown was found to be 39.8 -3.6% at MR¼20 before and 35.6 -4.55% after nebulization, comparable to results observed using unnebulized commercial transfection reagent, RNAiFect. Conclusions: SC12CDClickpropylamine nanocomplexes can be effectively nebulized for pulmonary delivery of siRNA using Aeroneb technology to mediate knockdown in airway cells. To the best of our knowledge, this is the first study examining the suitability of SC12CDClickpropylamine-siRNA nanocomplexes for pulmonary delivery. Furthermore, this work provides an integrated nanomedicine-device combination for future in vitro and in vivo preclinical and clinical studies of inhaled siRNA therapeutics.

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Section: Discussionmentioning

confidence: 86%

Section: Discussionmentioning

confidence: 99%

Early-Stage Development of Novel Cyclodextrin-siRNA Nanocomplexes Allows for Successful Postnebulization Transfection of Bronchial Epithelial Cells

Hibbitts

O’Mahony²,

Forde³

et al. 2014

Journal of Aerosol Medicine and Pulmonary Drug Delivery

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“…The level of uptake mediated by transfection complexes was assessed by flow cytometry [38]. Fluorescently labelled siRNA (Qiagen) was used for these experiments.…”

Section: Methodsmentioning

confidence: 99%

Cationic and PEGylated Amphiphilic Cyclodextrins: Co-Formulation Opportunities for Neuronal Sirna Delivery

et al. 2013

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Optimising non-viral vectors for neuronal siRNA delivery presents a significant challenge. Here, we investigate a co-formulation, consisting of two amphiphilic cyclodextrins (CDs), one cationic and the other PEGylated, which were blended together for siRNA delivery to a neuronal cell culture model. Co-formulated CD-siRNA complexes were characterised in terms of size, charge and morphology. Stability in salt and serum was also examined. Uptake was determined by flow cytometry and toxicity was measured by MTT assay. Knockdown of a luciferase reporter gene was used as a measure of gene silencing efficiency. Incorporation of a PEGylated CD in the formulation had significant effects on the physical and biological properties of CD.siRNA complexes. Co-formulated complexes exhibited a lower surface charge and greater stability in a high salt environment. However, the inclusion of the PEGylated CD also dramatically reduced gene silencing efficiency due to its effects on neuronal uptake. The co-formulation strategy for cationic and PEGylated CDs improved the stability of the CD.siRNA delivery systems, although knockdown efficiency was impaired. Future work will focus on the addition of targeting ligands to the co-formulated complexes to restore transfection capabilities.

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“…In addition, amphiphilic CyDs are also utilized not only as low-molecular-weight drug carriers or gene transfer carriers but also as siRNA carriers [115][116][117][118][119][120][121]. For example, amphiphilic b-CyD derivatives having cationic groups and lipophilic chains formed complexes with siRNA and achieved the neuronal siRNA delivery without toxicity [102,122]. Amphiphilic b-CyD derivatives also showed high TNF-a siRNA transfer activity both in vitro and in vivo, indicating the potential for the treatment of inflammatory bowel disease [123].…”

Section: Other Cyd-based Drug Carriers For Peptides and Proteinsmentioning

confidence: 99%

Recent advances in cyclodextrin delivery techniques

Arima

Hayashi

Higashi

et al. 2015

Expert Opinion on Drug Delivery

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To achieve the controlled release and/or targeting of low-molecular-weight drugs in systemic administration, the construction of novel CyDs and CyD the supramolecular system should be a useful approach because of the stable complexation of drugs with CyDs. In addition, the combination systems of CyDs and various carriers have the potential as advanced drug delivery systems for proteins and nucleic acids. Furthermore, CyDs have great potential as APIs for various diseases with few side effects, although the detailed mechanism, especially cellular uptake of CyDs, should be clarified.

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Characterisation of cationic amphiphilic cyclodextrins for neuronal delivery of siRNA: Effect of reversing primary and secondary face modifications

Cited by 25 publications

References 36 publications

Early-Stage Development of Novel Cyclodextrin-siRNA Nanocomplexes Allows for Successful Postnebulization Transfection of Bronchial Epithelial Cells

Early-Stage Development of Novel Cyclodextrin-siRNA Nanocomplexes Allows for Successful Postnebulization Transfection of Bronchial Epithelial Cells

Cationic and PEGylated Amphiphilic Cyclodextrins: Co-Formulation Opportunities for Neuronal Sirna Delivery

Recent advances in cyclodextrin delivery techniques

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