Numerical simulations of in vitro nanoparticle toxicity – The case of poly(amido amine) dendrimers

Maher, Marcus A.; Naha, Pratap C.; Mukherjee, Sourav P.; Byrne, Hugh J.

doi:10.1016/j.tiv.2014.07.014

Cited by 42 publications

(59 citation statements)

References 52 publications

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“…According to the description of "Operational models of pharmacological agonism" by Black and Leff (Black and Leff, 1983), the action is one of a partial agonist, and IC 50 represents the concentration at which half the maximum observed affect is elicited. A clear dose dependence is observable, and, as illustrated in Table 1, the IC 50 value decreases with increasing exposure time, indicative of a progressive toxic response, as, for example, experimentally demonstrated and numerically simulated using a phenomenological rate equation approach by Maher et al (2014), for the in vitro response to Poly (amido amide) (PAMAM) dendrimer exposure. Figure 3 shows the equivalent cytotoxic response for HeLa cells on the collagen matrices.…”

Section: Discussionmentioning

confidence: 88%

“…The dose dependent response of toxicity assays has been comprehensively described in the treatment by Black and Leff (Black and Leff, 1983) and, more recently, the phenomenological rate equation model of Maher et al (2014) demonstrated that the dose and time dependent responses can be reproduced by consideration of a complex cascade of events from the uptake of the external agent, to the registration of the cellular response by the cytotoxicological assay. The response profile is sensitive to the uptake rate, cellular reactions and the assay responses.…”

Section: Discussionmentioning

confidence: 99%

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Chemotherapeutic efficiency of drugs in vitro: Comparison of doxorubicin exposure in 3D and 2D culture matrices

Casey¹,

Gargotti²,

Bonnier

et al. 2016

Toxicology in Vitro

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The interest in the use of 3D matrices for in vitro analysis, with a view to increasing the relevance of in vitro studies and reducing the dependence on in vivo studies, has been growing in recent years.Cells grown in a 3D in vitro matrix environment have been reported to exhibit significantly different properties to those in a conventional 2D culture environment. However, comparison of 2D and 3D cell culture models have recently been noted to result in differing responses of cytotoxic assays, without any associated change in viability. The effect was attributed to differing conversion rates and effective concentrations of the resazurin assay in 2D and 3D environments, rather than differences in cellular metabolism. In this study, the efficacy of a chemotherapeutic agent, doxorubicin, is monitored and compared in conventional 2D and 3D collagen gel exposures of immortalized human cervical cells. Viability was monitored with the aid of the Alamar Blue assay and drug internalisation was verified using confocal microscopy. Drug uptake and retention within the collagen matrix was monitored by absorption spectroscopy. The viability studies showed apparent differences between the 2D and 3D culture systems, the differences attributed in part to the physical transition from 2D to a 3D environment causing alterations to dye resazurin uptake and conversion rates. The use of 3D culture matrices has widely been interpreted to result in "reduced" toxicity or cellular "resistance" to the chemotherapeutic agent. The results of this study show that the reduced efficiency of the drug to cells grown in the 3D environment can be accounted for by a sequential reduction of the effective concentration of the test compound and assay. This is due to absorption within the collagen gel inducing a higher uptake of both drug and assay thereby influencing the toxic impact of the drug and conversion rate of resazurin, and. the increased effective surface area of the cell exposed to the drug and assay in the 3D environment. The effect was noted to be higher after shorter exposure periods and should be accounted for in in vitro 2D and 3D culture environment comparisons.

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Section: Discussionmentioning

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Chemotherapeutic efficiency of drugs in vitro: Comparison of doxorubicin exposure in 3D and 2D culture matrices

Casey¹,

Gargotti²,

Bonnier

et al. 2016

Toxicology in Vitro

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“…Mitochondria exist within the cells in all stages of their DNA replication, and are first targeted by DOX which explains its earlier response and higher sensitivity. [45][46][47] Since cells will be analysed after 24 h exposure, the IC 50 determined using the MTT assay was used for the rest of the study.…”

Section: Cytotoxicity Assaysmentioning

confidence: 99%

Raman micro spectroscopy for in vitro drug screening: subcellular localisation and interactions of doxorubicin

Farhane

Bonnier

Casey

et al. 2015

Analyst

118

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Raman spectroscopy is used for the localization and tracking of chemotherapeutic drug, doxorubicin, in the intracellular environment of lung cancer cell line. Results show the potential of the technique to monitor the mechanisms of action and response on a molecular level, with subcellular resolution.Please check this proof carefully. Our staff will not read it in detail after you have returned it.Translation errors between word-processor files and typesetting systems can occur so the whole proof needs to be read. Please pay particular attention to: tabulated material; equations; numerical data; figures and graphics; and references. If you have not already indicated the corresponding author(s) please mark their name(s) with an asterisk. Please e-mail a list of corrections or the PDF with electronic notes attached -do not change the text within the PDF file or send a revised manuscript. Corrections at this stage should be minor and not involve extensive changes. All corrections must be sent at the same time.Please bear in mind that minor layout improvements, e.g. in line breaking, table widths and graphic placement, are routinely applied to the final version.We will publish articles on the web as soon as possible after receiving your corrections; no late corrections will be made. Please ensure that all queries are answered when returning your proof corrections so that publication of your article is not delayed. Vibrational spectroscopy, including Raman spectroscopy, has been widely used over the last few years to explore potential biomedical applications. Indeed, Raman spectroscopy has been demonstrated to be a powerful non-invasive tool in cancer diagnosis and monitoring. In confocal microscopic mode, the technique is also a molecularly specific analytical tool with optical resolution which has potential applications in subcellular analysis of biochemical processes, and therefore as an in vitro screening tool of the efficacy and mode of action of, for example, chemotherapeutic agents. In order to demonstrate and explore the potential in this field, established, model chemotherapeutic agents can be valuable. In study paper, Raman spectroscopy coupled with confocal microscopy were used for the localization and tracking of the commercially available drug, doxorubicin (DOX), in the intracellular environment of the lung cancer cell line, A549. Cytotoxicity assays were employed to establish clinically relevant drug doses for 24 h exposure, and confocal laser scanning fluorescence microscopy was conducted in parallel with Raman spectroscopy profiling to confirm the drug internalisation and localisation. Multivariate statistical analysis, consisting of PCA ( principal components analysis) was used to highlight doxorubicin interaction with cancer cells and spectral variations due to its effects before and after DOX spectral features subtraction from nuclear and nucleolar spectra, were compared to non-exposed control spectra. Results show that Raman micro spectroscopy is not only able to detect doxorubicin inside cells an...

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“…The effect of PAMAM dendrimer generation on their cytotoxicity was also investigated using an in vitro experiment that examined high-generation (G4, G5, and G6) PAMAM dendrimers (Mukherjee et al, 2010a(Mukherjee et al, , 2010bMaher et al, 2014). However, the wide range of PAMAM generations was not examined yet to elucidate the relationship between their generations and cytotoxicity.…”

Section: Introductionmentioning

confidence: 99%

Effects of PAMAM dendrimers with various surface functional groups and multiple generations on cytotoxicity and neuronal differentiation using human neural progenitor cells

et al. 2016

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-Polyamidoamine (PAMAM) dendrimers have potential for biological applications as delivery systems for genes, drugs, and imaging agents into the brain, but their developmental neurotoxicity remains unknown. We investigated the effects of PAMAM dendrimers with various surface functional groups and multiple generations on neuronal differentiation using human neural progenitor cells at an equal mass concentration. Only PAMAM dendrimers containing amine (NH 2 ) surface groups at concentrations of 10 μg/mL significantly reduced cell viability and neuronal differentiation, compared with non-amine-terminated dendrimers. PAMAM-NH 2 with generation (G)3, G4, G5 G6, and G7 significantly decreased cell viability and inhibited neuronal differentiation from a concentration of 5 μg/mL, but G0, G1, and G2 dendrimers did not have any effect at this concentration. Cytotoxicity indices of PAMAM-NH 2 dendrimers at 10 μg/mL correlated well with the zeta potentials of the particles. Surface group density and particle number in unit volume is more important characteristic than particle size to influence cytotoxicity for positive changed dendrimers. PAMAM-50% C 12 at 1 μg/mL altered the expression level of the oxidative stress-related genes, ROR1, CYP26A1, and TGFB1, which is a DNA damage response gene. Our results indicate that PAMAM dendrimer exposure may have a surface charge-dependent adverse effect on neuronal differentiation, and that the effect may be associated with oxidative stress and DNA damage during development of neural cells.

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Numerical simulations of in vitro nanoparticle toxicity – The case of poly(amido amine) dendrimers

Cited by 42 publications

References 52 publications

Chemotherapeutic efficiency of drugs in vitro: Comparison of doxorubicin exposure in 3D and 2D culture matrices

Chemotherapeutic efficiency of drugs in vitro: Comparison of doxorubicin exposure in 3D and 2D culture matrices

Raman micro spectroscopy for in vitro drug screening: subcellular localisation and interactions of doxorubicin

Effects of PAMAM dendrimers with various surface functional groups and multiple generations on cytotoxicity and neuronal differentiation using human neural progenitor cells

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