In vitro mammalian cytotoxicological study of PAMAM dendrimers – Towards quantitative structure activity relationships

Mukherjee, Sourav P.; Davoren, Maria; Byrne, Hugh J.

doi:10.1016/j.tiv.2009.09.014

Cited by 140 publications

(127 citation statements)

References 40 publications

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“…The lower initial value of 170 the PAMAM G6 dendrimers was used due to their reported EC 50 value being much lower than 171 their G4 counterparts. 7,8,9 Dose dependent viability percentages were calculated at time points: 6, 172 12, 24, 48 and 72 hours. Percentage viability was calculated as compared to a control which had 173 been exposed to 200μM BSO, but had no nanoparticle treatment; this was to ensure any changes 174 were caused by the nanoparticle and were not the result of BSO treatment.…”

Section: Viability Assays 165mentioning

confidence: 99%

“…The MTT results show a dramatically different dose dependent cytotoxicity 330 profile for the BSO dosed cells compared to un-dosed. 7 At 6 hours exposure (Figure 4b), the 331 viability is seen to be reduced to around 80% over the entire dose range. However, at exposure 332 times of 12, 24, 48 and 72 hours, increases in viability are seen for the low-medium dose range.…”

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confidence: 97%

“…8 All confocal images were analysed using ImageJ and co-localisation 231 studies were performed using Manders split coefficients calculated with the JaCoP plugin for 232 and subsequent ROS generation at the endosomal sites. 6,7,8,9 Co-localisation (performed on the 274 images in Figure 1) shows that 91(±3)% of the generated ROS occurs in the neighbourhood of 275 endosomes, and that 71(±4)% of endosomal formation resulted in increases in ROS production 276…”

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confidence: 99%

“…7,8 This process may be accelerated via the 521 opening of the mitochondrial membrane permeability transition pore. 30,31,32 Whether passively 522 diffused into the cell, or released into the cytosol by endosomolysis after endocytosis, the result 523 of free PAMAM dendrimers in the cytosol and subsequent localisation to the mitochondria 524 should be equivalent, both resulting in disruption of the mitochondria, a second phase increase in 525 ROS within the cell, subsequent decay in the mitochondrial membrane potential and finally the 526 initiation of a cascade leading to apoptosis.…”

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confidence: 99%

“…30,31,32 Whether passively 522 diffused into the cell, or released into the cytosol by endosomolysis after endocytosis, the result 523 of free PAMAM dendrimers in the cytosol and subsequent localisation to the mitochondria 524 should be equivalent, both resulting in disruption of the mitochondria, a second phase increase in 525 ROS within the cell, subsequent decay in the mitochondrial membrane potential and finally the 526 initiation of a cascade leading to apoptosis. 7,8,9,10 It should also be noted that in both cases the 527 opening of the mitochondrial membrane transition pore occurs, either by the action of 528 BSO,30,31,32 or due to the release of the endosomal/lysosomal contents causing intracellular 529 release of Ca 2+ , leading to calcium dependant opening of the pore. 21 This would, in both cases, 530 facilitate the entry of the dendrimer to the mitochondria.…”

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confidence: 99%

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Modification of the in vitro uptake mechanism and antioxidant levels in HaCaT cells and resultant changes to toxicity and oxidative stress of G4 and G6 poly(amidoamine) dendrimer nanoparticles

Maher¹,

Byrne²

2016

Anal Bioanal Chem

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20The mechanism of cellular uptake by endocytosis and subsequent oxidative stress has been 21 identified as the paradigm for the toxic response of cationically surface charged nanoparticles. In 22 an attempt to circumvent the process, the effect of increased cellular membrane permeability on 23 the uptake mechanisms of poly (amidoamine) dendrimers generation 4 (G4) and 6 (G6) in vitro 24 was investigated. Immortalised, non-cancerous human keratinocyte (HaCaT) cells were treated 25 with DL-Buthionine-(S,R)-sulfoximine (BSO). Active uptake of the particles was monitored 26 using fluorescence microscopy to identify and quantify endosomal activity and resultant 27 oxidative stress, manifest as increased levels of reactive oxygen species, monitored using the 28 carboxy-H 2 DCFDA dye. Dose dependent cytotoxicity for G4 and G6 exposure was registered 29 using the cytotoxicity assays Alamar Blue and MTT, from 6 to 72 hours. 30Reduced uptake by endocytosis is observed for both dendrimer species. A dramatic change, 31 compared to untreated cells, is observed in the cytotoxic and oxidative stress response of the 32 BSO treated cells. The significantly increased mitochondrial activity, dose dependent anti-33 oxidant behaviour and reduced degree of endocytosis for both dendrimer generations, in BSO 34 treated cells, indicates enhanced permeability of the cell membrane, resulting in the passive, 35 diffusive uptake of dendrimers, replacing endocytosis as the primary uptake mechanism. The 36 complex MTT response reflects the importance of glutathione in maintaining redox balance 37 within the mitochondria. The study highlights the importance of regulation of this redox balance 38 for cell metabolism, but also points to the potential of controlling the nanoparticle uptake 39 mechanisms, and resultant cytotoxicity, with implications for nanomedicine. 40 41 3

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Section: Viability Assays 165mentioning

confidence: 99%

mentioning

confidence: 97%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Modification of the in vitro uptake mechanism and antioxidant levels in HaCaT cells and resultant changes to toxicity and oxidative stress of G4 and G6 poly(amidoamine) dendrimer nanoparticles

Maher¹,

Byrne²

2016

Anal Bioanal Chem

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Polymeric Nanoparticles

Vasilakes¹,

Dziubla²,

Wattamwar³

2013

Engineering Polymer Systems for Improved Drug Delivery

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Enhancement of octreotide antiproliferative activity by PEGylated PAMAM dendrimers delivery

Díaz,

Cifuentes,

Oyarzún

et al. 2024

J of Applied Polymer Sci

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PEGylated PAMAM dendrimers (PEG‐PAMAM) are well‐characterized biomaterials with still unexplored applications as carriers of drugs acting via membrane receptors, such as octreotide. This work confirmed the safety and negligible internalization capacity of fourth‐generation 50%‐PEG‐PAMAM in HEK‐293 cells, to then assessed their supramolecular binding to octreotide through tryptophan quenching experiments and Gaussian‐accelerated molecular dynamics (GaMD) simulations. Tryptophan quenching showed that PEG‐PAMAM binds octreotide with a Kbind of 6 × 106 M−1 and a complex stoichiometry of 1:1.4, unlike native PAMAM. GaMD simulations revealed that octreotide binds at the outer PEG shell of PEG‐PAMAM, potentially hindering the drug from proteolytic degradation and enabling its release at a membrane level. Viability experiments on HeLa, PC‐12, and HEK‐293 cells incubated with increasing concentrations of octreotide in free drug solutions and equimolar mixtures with PEG‐PAMAM confirmed that the PEGylated dendrimer acts as an efficient supramolecular carrier for octreotide and enhances the antiproliferative effects of the drug. Our findings highlight a novel facet for PEG‐PAMAM dendrimers as macromolecular vehicles for peptide or non‐peptide drugs acting via membrane receptor sites.

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In vitro mammalian cytotoxicological study of PAMAM dendrimers – Towards quantitative structure activity relationships

Cited by 140 publications

References 40 publications

Modification of the in vitro uptake mechanism and antioxidant levels in HaCaT cells and resultant changes to toxicity and oxidative stress of G4 and G6 poly(amidoamine) dendrimer nanoparticles

Modification of the in vitro uptake mechanism and antioxidant levels in HaCaT cells and resultant changes to toxicity and oxidative stress of G4 and G6 poly(amidoamine) dendrimer nanoparticles

Polymeric Nanoparticles

Enhancement of octreotide antiproliferative activity by PEGylated PAMAM dendrimers delivery

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