In vitro toxicity and permeation of cyclodextrins in Calu-3 cells

Matilainen, Laura; Toropainen, Tarja; Vihola, Henna; Hirvonen, Jouni; Järvinen, Tomi; Jarho, Pekka; Järvinen, Kristiina

doi:10.1016/j.jconrel.2007.11.003

Cited by 71 publications

(33 citation statements)

References 36 publications

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“…(13,38) This would indicate a dose-dependent relationship with regard to SC12CDClick-propylamine-siRNA nanocomplex-mediated toxicity, which has also been seen in unmodified CD delivery to Calu-3 cells. (42) Finally, this high level of cell viability was found to be in contrast to previous studies indicating the cytotoxic nature of preexisting transfection agents such as PEI and RNAiFect-siRNA nanocomplexes. (13,43) With specific regard to RNAiFect, Arima et al found that although well tolerated at MR £ 6, RNAiFect-siRNA nanocomplexes resulted in decreases in cell viability of up to 60% when MRs increased up to MR = 10.…”

Section: Discussioncontrasting

confidence: 68%

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: Discussioncontrasting

confidence: 68%

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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“…These phenomena may be attributed to the inclusion of cholesterol on the cell membrane by CyD. 30,31 The relationship between the transfection efficiency and the N/P ratio of PEI 600 -β-CyD on MSCs is proportional when the N/P ratio ranges from 10 to 30. The highest transfection efficiency is achieved when the N/P ratio is 30.…”

Section: Discussionmentioning

confidence: 99%

Polyethylenimine600-β-cyclodextrin: a promising nanopolymer for nonviral gene delivery of primary mesenchymal stem cells

Tong¹,

Huang²,

Shi³

et al. 2013

IJN

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Genetically modified mesenchymal stem cells (MSCs) have great potential in the application of regenerative medicine and molecular therapy. In the present manuscript, we introduce a nanopolymer, polyethylenimine 600 -β-cyclodextrin (PEI 600 -β-CyD), as an efficient polyplex-forming plasmid delivery agent with low toxicity and ideal transfection efficiency on primary MSCs. PEI 600 -β-CyD causes significantly less cytotoxicity and apoptosis on MSCs than 25 kDa high-molecular-weight PEI (PEI25kDa). PEI 600 -β-CyD also exhibits similar transfection efficiency as PEI25kDa on MSCs, which is higher than that of PEI600Da. Quantum dot-labeled plasmids show that PEI 600 -β-CyD or PEI25kDa delivers the plasmids in a more scattered manner than PEI600Da does. Further study shows that PEI 600 -β-CyD and PEI25kDa are more capable of delivering plasmids into the cell lysosome and nucleus than PEI600Da, which correlates well with the results of their transfection-efficiency assay. Moreover, among the three vectors, PEI 600 -β-CyD has the most capacity of enhancing the alkaline phosphatase activity of MSCs by transfecting bone morphogenetic protein 2, 7, or special AT-rich sequence-binding protein 2. These results clearly indicate that PEI 600 -β-CyD is a safe and effective candidate for the nonviral gene delivery of MSCs because of its ideal inclusion ability and proton sponge effect, and the application of this nanopolymer warrants further investigation.

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“…Furthermore, some interesting abilities of cyclodextrins, such as permeability enhancer, could be evaluated by quantifying cyclodextrin content before and after their passage through a cell layer (Matilainen et al, 2008). Since Nuclear Magnetic Resonance (NMR) spectroscopy is one of the most widely used techniques for understanding the interaction between CD and guest compounds (Bertholet et al, 2005;Higashi et al, 2009;Lis-Cieplak et al, 2014;Malet-Martino and Holzgrabe, 2011;Schneider et al, 1998;Vogt and Strohmeier, 2012;Yang et al, 2009) and to evaluate the number of substituted glucopyranose units (molar substitution), we aim to apply 1 H nuclear magnetic resonance spectroscopy ( 1 H NMR) to quantify 2-HP-b-CD in pharmaceutical solutions.…”

Section: Introductionmentioning

confidence: 99%

Rapid quantification of 2-hydroxypropyl-β-cyclodextrin in liquid pharmaceutical formulations by 1H nuclear magnetic resonance spectroscopy

Dufour

Évrard

Tullio

2015

European Journal of Pharmaceutical Sciences

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a b s t r a c tQuantification of 2-hydroxypropyl-b-cyclodextrin (2-HP-b-CD) is not yet described in United States Pharmacopeia (USP) and European Pharmacopeia (EP). A useful quality control tool is therefore needed for the specific quantification in finished liquid pharmaceutical products, especially for formulations containing 2-HP-b-CD as an active ingredient. A new technique is also mandatory for the development of future formulations in which 2-HP-b-CD concentration could influence the properties of these formulations. Here, we described the use of 1 H NMR for the rapid quantification of 2-HP-b-CD directly into pharmaceutical solutions without any extraction or separation steps. This technique was successfully applied to different pharmaceutical solutions comprising an i.v. solution (budesonide/2-HP-b-CD complex), an eye drop solution (Indocollyre Ò ) and an oral solution (Sporanox Ò ). Specificity, linearity, precision (repeatability and intermediate precision), trueness, limits of quantification (LOQs) and accuracy were used as validation criteria.

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In vitro toxicity and permeation of cyclodextrins in Calu-3 cells

Cited by 71 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

Polyethylenimine600-β-cyclodextrin: a promising nanopolymer for nonviral gene delivery of primary mesenchymal stem cells

Rapid quantification of 2-hydroxypropyl-β-cyclodextrin in liquid pharmaceutical formulations by 1H nuclear magnetic resonance spectroscopy

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In vitro toxicity and permeation of cyclodextrins in Calu-3 cells

Cited by 71 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

Polyethylenimine600-&beta;-cyclodextrin: a promising nanopolymer for nonviral gene delivery of primary mesenchymal stem cells

Rapid quantification of 2-hydroxypropyl-β-cyclodextrin in liquid pharmaceutical formulations by 1H nuclear magnetic resonance spectroscopy

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Polyethylenimine600-β-cyclodextrin: a promising nanopolymer for nonviral gene delivery of primary mesenchymal stem cells