Predicting cytotoxicity of PAMAM dendrimers using molecular descriptors.
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ABSTRACT:
SUBMITTER: Jones DE
PROVIDER: S-EPMC4660915 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:We are presenting here the application of toxicogenomics to perform the evaluation of toxic effects of two polyamidoamine dendrimers (Generation3 and Generation4) on the developing zebrafish embryo. They are nanomaterials of special concern under the toxicological point of view because of their relatively high solubility in water and bioavailability. Zebrafish embryo toxicity assays (zFET) showed that G3 was more toxic to zebrafish than G4, and that both compounds were several orders of magnitude more toxic than other carbonaceous nanomaterials, like carbon fullerenes or nanotubes. The results suggest a variety of MoA for different dendrimers, probably related to the nature and number of the chemical groups attached to their surface. They also confirm the relatively high bioavailability of these compounds, a key factor for the assessment of the risk associated to their use and release into the environment. About 5% genes were affected by the treatment. Gene ontology (GO) analyses show that these genes are involved in the oxidation-reduction process and also in the nervous system development. Representatives of each GO functional groups were selected and quantified by real-time PCR to validate the microarray data and to differentiate the action of generations of dendrimers studied.
2013-11-12 | GSE41333 | GEO
Project description:Electrostatic interactions play a pivotal role in the structure and mechanism of action of most biomolecules. There are several conceptually different methods to deal with electrostatics in molecular dynamics simulations. Ionic strength effects are usually introduced using such methodologies and can have a significant impact on the quality of the final conformation space obtained. We have previously shown that full system neutralization can lead to wrong lipidic phases in the 25% PA/PC bilayer (J. Chem. Theory Comput. 2014,10, 5483-5492). In this work, we investigate how two limit approaches to the ionic strength treatment (implicitly with GRF or using full system neutralization with either GRF or PME) can influence the conformational space of the second-generation PAMAM dendrimer. Constant-pH MD simulations were used to map PAMAM's conformational space at its full pH range (from 2.5 to 12.5). Our simulations clearly captured the coupling between protonation and conformation in PAMAM. Interestingly, the dendrimer conformational distribution was almost independent of the ionic strength treatment methods, which is in contrast to what we have observed in charged lipid bilayers. Overall, our results confirm that both GRF with implicit ionic strength and a fully neutralized system with PME are valid approaches to model charged globular systems, using the GROMOS 54A7 force field.
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Project description:Poly(amidoamine) (PAMAM) dendrimers have been proposed for a variety of biomedical applications and are increasingly studied as model nanomaterials for such use. The dendritic structure features both modular synthetic control of molecular size and shape and presentation of multiple equivalent terminal groups. These properties make PAMAM dendrimers highly functionalizable, versatile single-molecule nanoparticles with a high degree of consistency and low polydispersity. Recent nanotoxicological studies showed that intravenous administration of amine-terminated PAMAM dendrimers to mice was lethal, causing a disseminated intravascular coagulation-like condition. To elucidate the mechanisms underlying this coagulopathy, in vitro assessments of platelet functions in contact with PAMAM dendrimers were undertaken. This study demonstrates that cationic G7 PAMAM dendrimers activate platelets and dramatically alter their morphology. These changes to platelet morphology and activation state substantially altered platelet function, including increased aggregation and adherence to surfaces. Surprisingly, dendrimer exposure also attenuated platelet-dependent thrombin generation, indicating that not all platelet functions remained intact. These findings provide additional insight into PAMAM dendrimer effects on blood components and underscore the necessity for further research on the effects and mechanisms of PAMAM-specific and general nanoparticle toxicity in blood.
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Project description:Intrinsic, non-traditional fluorescence of polyamidoamine (PAMAM) dendrimers that do not possess classical fluorophores has been attracting considerable interest for the last decade. Many hypotheses regarding the source of the fluorescence have appeared, but some of them are still disputable. In order to shed new light on the nature of the phenomenon, we applied quenchers that are normally used to study intrinsic fluorescence of proteins (i.e., KI, CsCl, and acrylamide). KI and acrylamide efficiently quenched steady state fluorescence of PAMAM G2, PAMAM G3, and PAMAM G4 dendrimers. Stern-Volmer plots exhibited a downward curvature that has been elucidated by heterogenous emission. We assume that there are two distinct fluorescent moieties in the dendrimer structure that are characterized by different accessibility to the quenchers.
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Project description:Poly(amido amine) (PAMAM) dendrimers have been considered as possible delivery systems for anticancer drugs. One potential advantage of these carriers would be their use in oral formulations, which will require absorption in the intestinal lumen. This may require the opening of tight junctions which may be enabled by reducing the Ca2+ concentration in the intestinal lumen, which has been shown as an absorption mechanism for EDTA (ethylenediaminetetraacetic acid). Using molecular dynamics simulations, we show that the G3.5 PAMAM dendrimers are able to chelate Ca2+ at similar proportions to EDTA, providing support to the hypothesis that oral formulations of PAMAM dendrimers could use this high chelating efficiency as a potential mechanism for permeating the tight junctions of the intestines if other formulation barriers could be overcome.
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Project description:We are presenting here the application of toxicogenomics to perform the evaluation of toxic effects of two polyamidoamine dendrimers (Generation3 and Generation4) on the developing zebrafish embryo. They are nanomaterials of special concern under the toxicological point of view because of their relatively high solubility in water and bioavailability. Zebrafish embryo toxicity assays (zFET) showed that G3 was more toxic to zebrafish than G4, and that both compounds were several orders of magnitude more toxic than other carbonaceous nanomaterials, like carbon fullerenes or nanotubes. The results suggest a variety of MoA for different dendrimers, probably related to the nature and number of the chemical groups attached to their surface. They also confirm the relatively high bioavailability of these compounds, a key factor for the assessment of the risk associated to their use and release into the environment. About 5% genes were affected by the treatment. Gene ontology (GO) analyses show that these genes are involved in the oxidation-reduction process and also in the nervous system development. Representatives of each GO functional groups were selected and quantified by real-time PCR to validate the microarray data and to differentiate the action of generations of dendrimers studied. Two different treatments were performed in this study. Zebrafish fertlized eggs were exposed to PAMAM dendrimer G3 and G4 during 48h. 3 biological replicates per studied dendrimer are included such as each control sample.
2013-11-12 | E-GEOD-41333 | biostudies-arrayexpress
Project description:Poly(amidoamine) (PAMAM) dendrimers are increasingly studied as model nanoparticles for a variety of biomedical applications, notably in systemic administrations. However, with respect to blood-contacting applications, amine-terminated dendrimers have recently been shown to activate platelets and cause a fatal, disseminated intravascular coagulation (DIC)-like condition in mice and rats. We here demonstrate that, upon addition to blood, cationic G7 PAMAM dendrimers induce fibrinogen aggregation, which may contribute to the in vivo DIC-like phenomenon. We demonstrate that amine-terminated dendrimers act directly on fibrinogen in a thrombin-independent manner to generate dense, high-molecular-weight fibrinogen aggregates with minimal fibrin fibril formation. In addition, we hypothesize this clot-like behavior is likely mediated by electrostatic interactions between the densely charged cationic dendrimer surface and negatively charged fibrinogen domains. Interestingly, cationic dendrimers also induced aggregation of albumin, suggesting that many negatively charged blood proteins may be affected by cationic dendrimers. To investigate this further, zebrafish embryos were employed to more specifically determine the speed of this phenomenon and the pathway- and dose-dependency of the resulting vascular occlusion phenotype. These novel findings show that G7 PAMAM dendrimers significantly and adversely impact many blood components to produce rapid coagulation and strongly suggest that these effects are independent of classic coagulation mechanisms. These results also strongly suggest the need to fully characterize amine-terminated PAMAM dendrimers in regard to their adverse effects on both coagulation and platelets, which may contribute to blood toxicity.
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Project description:The desire to synthesize soft supramolecular structures with size scales similar to biological systems has led to work in assembly of polymeric nanomaterials. Recent advances in the isolation of generationally homogenous poly(amidoamine) (PAMAM) dendrimer enables their use as quantized building blocks. Here, we report their assembly into precise nanoclusters. In this work, click-functional ligands are stochastically conjugated to monomeric generation 5 PAMAM dendrimer and separated via reverse-phase HPLC to isolate dendrimers with precise numbers of click ligands per dendrimer particle. The click-ligand/dendrimer conjugates are then employed as modular building blocks for the synthesis of defined nanostructures. Complimentary click chemistry employing dendrimers with 1, 2, 3, or 4 ring-strained cyclooctyne ligands and dendrimers with 1 azide ligand were utilized to prepare megamer structures containing 2 to 5 ~30,000 kDa monomer units as characterized by mass spectrometry, size exclusion chromatography, and reverse-phase liquid chromatography. The resulting structures are flexible with masses ranging from 60,000 to 150,000 kDa, and are soluble in water, methanol, and dimethylsulfoxide.
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Project description:The in vivo effects of nasal exposure to polyamidoamine (PAMAM) dendrimers on their effects on gene expression in the mouse brain. A single dose of PAMAM dendrimers or saline (control) was intranasally administered to 8-week old male BALB/c mice.
2014-03-26 | GSE56159 | GEO
Project description:Generation 3 (G3) PAMAM dendrimers are symmetrical, highly branched polymers widely reported in the scientific literature as therapeutic agents themselves or as carrier scaffolds for various therapeutic agents. A large number of analytical techniques have been applied to study PAMAM dendrimers, but one that has been missing is in-line reversed phase LC electrospray ionization mass spectrometry (RP/LC/ESI/MS). To translate PAMAM dendrimers into therapeutic agents, a better understanding of their purity, stability and structure is required, and in-line RP/LC/ESI/MS is widely applied to all three of these analytical questions. In this study, we developed a robust in-line RP/LC/ESI/MS method for assessing stability, purity and structure of the G3 PAMAM dendrimers, and we also examined the reasons why previous attempts at method development failed. Using the RP/LC/ESI/MS method we uncovered several unique aspects of the chemistry of G3 PAMAM dendrimers. They are interconverted between two isomeric forms by dialysis, and under higher concentration levels there is an inter-molecular displacement reaction resulting, which degrades PAMAM dendrimers. Purification of G3 dendrimers by RP/LC was also previously unreported; so we slightly modified the LC/MS method for isolating individual components from a complex dendrimer mixture. Thus, we have developed a robust, comprehensive method for characterizing PAMAM dendrimers and their degradation.
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