The effect of surface functionality on cellular trafficking of dendrimers

Perumal, Omathanu; Inapagolla, Rajyalakshmi; Kannan, Sujatha; Kannan, Rangaramanujam M.

doi:10.1016/j.biomaterials.2008.04.038

Cited by 349 publications

(321 citation statements)

References 50 publications

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“…43 On the other hand, Perumal et al found that uptake of cationic G4NH 3 dendrimers by A549 cells plateaus off after 1 hour, while uptake of anionic G3.5COOH dendrimers and neutral G4OH dendrimers increased more or less linearly over the duration of treatment. 44 On the basis of the kinetic data, we defined 2 hours as the incubation time, ensuring uptake sufficient to allow further …”

Section: Resultsmentioning

confidence: 99%

Uptake and intracellular traffic of siRNA dendriplexes in glioblastoma cells and macrophages

Perez¹,

Cosaka²,

Romero³

et al. 2011

IJN

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Background: Gene silencing using small interfering RNA (siRNA) is a promising new therapeutic approach for glioblastoma. The endocytic uptake and delivery of siRNA to intra cellular compartments could be enhanced by complexation with polyamidoamine dendrimers. In the present work, the uptake mechanisms and intracellular traffic of siRNA/generation 7 dendrimer complexes (siRNA dendriplexes) were screened in T98G glioblastoma and J774 macrophages. Methods: The effect of a set of chemical inhibitors of endocytosis on the uptake and silenc ing capacity of dendriplexes was determined by flow cytometry. Colocalization of fluorescent dendriplexes with endocytic markers and occurrence of intracellular dissociation were assessed by confocal laser scanning microscopy. Results: Uptake of siRNA dendriplexes by T98G cells was reduced by methylβcyclodextrin, and genistein, and cytochalasine D, silencing activity was reduced by genistein; dendriplexes colocalized with cholera toxin subunit B. Therefore, caveolindependent endocytosis was involved both in the uptake and silencing activity of siRNA dendriplexes. On the other hand, uptake of siRNA dendriplexes by J774 cells was reduced by methylβcyclodextrin, genistein, chlorpromazine, chloroquine, cytochalasine D, and nocodazole, the silencing activity was not affected by chlorpromazine, genistein or chloroquine, and dendriplexes colocalized with transferrin and cholera toxin subunit B. Thus, both clathrindependent and caveolindependent endocytosis mediated the uptake and silencing activity of the siRNA dendriplexes. SiRNA dendriplexes were internalized at higher rates by T98G but induced lower silencing than in J774 cells. SiRNA dendriplexes showed relatively slow dissociation kinetics, and their escape towards the cytosol was not mediated by acidification independently of the uptake pathway. Conclusion: The extent of cellular uptake of siRNA dendriplexes was inversely related to their silencing activity. The higher silencing activity of siRNA dendriplexes in J774 cells could be ascribed to the contribution of clathrindependent and caveolindependent endocytosis vs only caveolindependent endocytosis in T98G cells.

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Section: Resultsmentioning

confidence: 99%

Uptake and intracellular traffic of siRNA dendriplexes in glioblastoma cells and macrophages

Perez¹,

Cosaka²,

Romero³

et al. 2011

IJN

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“…However, it should be taken into account that the erythrocytes were incubated with dendrimers for 0.5 h and this time may have been too short to observe a stronger influence of VPD on lipid membranes. By comparison, PAMAM were shown to be bound to the cell membrane at about 1 h after exposure [54].…”

Section: Discussionmentioning

confidence: 97%

“…By contrast, dendrimers such as PAMAM and cationic phosphorus dendrimers carry a large number of positive charges at the surface of the dendritic structure, which can easily interact with plasma membranes [47,49]. Furthermore, according to a current theory, dendrimers can enter the cell via clathrin-dependent endocytosis and/or macropinocytosis [50][51][52][53] and the process of dendrimer uptake has been shown to reach completion within 4 h [52][53][54]. Therefore, it is possible that VPD are internalized into the cell within the first hours after treatment, causing minor, reversible changes in the cell membrane integrity, which are repaired during the next hours and undetectable at 24 h. Ciepluch et al [26] demonstrated that only VPD2 and VPD3 at the highest concentrations caused a small but statistically significant decrease in erythrocyte membrane fluidity, which implies that these VPD can interact with the polar headgroup region of the phospholipid bilayer.…”

Section: Discussionmentioning

confidence: 99%

Viologen-phosphorus dendrimers exhibit minor toxicity against a murine neuroblastoma cell line

Łaźniewska

Miłowska

Katir

et al. 2013

Cellular and Molecular Biology Letters

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Dendrimers containing viologen (derivatives of 4,4'-bipyridyl) units in their structure have been demonstrated to exhibit antiviral activity against human immunodeficiency virus (HIV-1). It has also recently been revealed that novel dendrimers with both viologen units and phosphorus groups in their structure show different antimicrobial, cytotoxic and hemotoxic properties, and have the ability to influence the activity of cholinesterases and to inhibit α-synuclein fibrillation. Since the influence of viologen-phosphorus structures on basic cellular processes had not been investigated, we examined the impact of such macromolecules on the murine neuroblastoma cell line (N2a). We selected three water-soluble viologen-phosphorus (VPD) dendrimers, which differ in their core structure, number of viologen units and number and type of surface groups, and analyzed several aspects of the cellular response. These included cell viability, generation of reactive oxygen species (ROS), alterations in mitochondrial activity, morphological modifications, and the induction of apoptosis and necrosis. The MTT assay results suggest that all of the tested dendrimers are only slightly cytotoxic. Although some changes in ROS formation and mitochondrial function were detected, the three compounds did not induce apoptosis or necrosis. In light of these results, we can assume that the tested VPD are relatively safe for mouse neuroblastoma cells. Although more research on their safety is needed, VPD seem to be promising nanoparticles for further biomedical investigation.

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“…Indeed, our data indicates that the hypertonic media induced decrease in CD.DNA uptake was due to non-specific inhibition of macropinocytosis. Hypertonic media has been previously reported to inhibit the uptake of the fluid phase endocytosis marker horseradish peroxidase (Carpentier et al 1989) and a number of other studies have commented on its lack of specificity (Perumal et al 2008). Therefore, CME is unlikely to be involved in the uptake of CD.DNA complexes by Caco-2 cells.…”

Section: Discussionmentioning

confidence: 97%

Mechanistic studies on the uptake and intracellular trafficking of novel cyclodextrin transfection complexes by intestinal epithelial cells

Neill

Guo

Byrne

et al. 2011

International Journal of Pharmaceutics

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The effect of surface functionality on cellular trafficking of dendrimers

Cited by 349 publications

References 50 publications

Uptake and intracellular traffic of siRNA dendriplexes in glioblastoma cells and macrophages

Uptake and intracellular traffic of siRNA dendriplexes in glioblastoma cells and macrophages

Viologen-phosphorus dendrimers exhibit minor toxicity against a murine neuroblastoma cell line

Mechanistic studies on the uptake and intracellular trafficking of novel cyclodextrin transfection complexes by intestinal epithelial cells

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