Interaction of Poly(amidoamine) Dendrimers with Supported Lipid Bilayers and Cells:  Hole Formation and the Relation to Transport

Hong, Seungpyo; Bielinska, Anna U.; Mecke, Almut; Keszler, B.; Beals, John M.; Shi, Xiangyang; Balogh, Lajos; Orr, Bradford G.; Baker, James R.; Holl, Mark M. Banaszak

doi:10.1021/bc049962b

Cited by 574 publications

(756 citation statements)

References 24 publications

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“…The former mechanism can lead to cell death due to loss of membrane polarization and/or leakage of ions and molecules into/out of the cell. To establish whether 'striped' nanoparticles penetrate cell membranes through creation of transient holes, we tested whether the internalization of ligand-protected nanoparticles was accompanied by escape of cytosol-localized tracer dye or conversely, cytosolic entry of an initially extracellular tracer dye 41,42 . First, DC2.4 cells were co-incubated with nanoparticles and calcein; calcein remains in endolysosomal compartments in cells unless it is co-internalized with a membrane-disrupting agent 43 .…”

mentioning

confidence: 99%

Surface-structure-regulated cell-membrane penetration by monolayer-protected nanoparticles

Verma¹,

Uzun²,

et al. 2008

Nature Mater

1,195

1,203

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Nanoscale objects are typically internalized by cells into membrane-bounded endosomes and fail to access the cytosolic cell machinery. Whereas some biomacromolecules may penetrate or fuse with cell membranes without overt membrane disruption, no synthetic material of comparable size has shown this property yet. Cationic nano-objects pass through cell membranes by generating transient holes, a process associated with cytotoxicity. Studies aimed at generating cell-penetrating nanomaterials have focused on the effect of size, shape and composition. Here, we compare membrane penetration by two nanoparticle 'isomers' with similar composition (same hydrophobic content), one coated with subnanometre striations of alternating anionic and hydrophobic groups, and the other coated with the same moieties but in a random distribution. We show that the former particles penetrate the plasma membrane without bilayer disruption, whereas the latter are mostly trapped in endosomes. Our results offer a paradigm for analysing the fundamental problem of cell-membrane-penetrating bio-and macro-molecules. Nanomaterials are of great interest for use in biomedicine as imaging tools 1-3 , phototherapy agents 4,5 and gene delivery carriers 6,7 . Their interactions with cell membranes are of central importance for all such applications. For example, many drugdelivery systems are based on the transport of therapeutic agents to the cytosol or nucleus of cells by nanoparticles; efficient delivery must be achieved while avoiding cytotoxicity during passage through cell membranes to reach intracellular target compartments 8,9 . Indeed, membrane penetration by synthetic 10 as well as by biologically derived 11 molecules/particles is currently under intense investigation. Some biomacromolecules, such as cell-penetrating peptides (CPPs), may be capable of penetrating membranes without overt lipid bilayer disruption/poration 12-15 . Likewise, synthetic nanomaterials with very small dimensions (molecules, metal nanoclusters 16 , small dendrimers 10 and carbon nanotubes 17 ) can also pass through cell membranes. However, to the best of our knowledge, no synthetic material larger than a few nanometres in size can pass through membranes without disrupting the integrity of these biological barriers. For example, charged particles (such as cationic quantum dots or dendrimers, mostly assisted by some degree of hydrophobicity) induce transient poration of cell membranes to enter cells, a process associated with cytotoxicity 18 . Alternatively, nanoparticles have been designed to explicitly disrupt endolysosomal membranes to enter the cell by force 19 or enter the cell aided by exogenous agents such as CPP chaperones 20 . In contrast, most nanoparticles are trapped in endosomes 21 and hence do not reach the cytosol.The surface properties of nanomaterials play a critical role in determining the outcome of their interactions with cells 22 . Recently, we found that when gold nanoparticles are coated with binary mixtures of hydrophobic and hydrophilic organic mo...

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mentioning

confidence: 99%

Surface-structure-regulated cell-membrane penetration by monolayer-protected nanoparticles

Verma¹,

Uzun²,

et al. 2008

Nature Mater

1,195

1,203

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“…This observation was similar to the ndings reported in previous numerical and experimental studies of the interactions between an un-acetylated G5 dendrimer and a DPPC lipid bilayer, 18 a DMPC lipid bilayer 33 and cell membranes (KB and Rat2). 34 The experimental results indicated that the pore formation during the interactions of the dendrimer-DMPC lipid bilayer was caused by the removal of lipid molecules from the supported substrate by the dendrimers, resulting in a composite of dendrimers and lipids. 33 During the inner interaction, similar to the G4 dendrimer, the G5 dendrimer was also adsorbed tightly onto the inner leaet of the membrane.…”

Section: Interactions Between the G5 Dendrimer And Asymmetric Membranesmentioning

confidence: 96%

Molecular analysis of interactions between dendrimers and asymmetric membranes at different transport stages

et al. 2014

Soft Matter

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Studying dendrimer-biomembrane interactions is important for understanding drug and gene delivery. In this study, coarse-grained molecular dynamics simulations were performed to investigate the behaviors of polyamidoamine (PAMAM) dendrimers (G4 and G5) as they interacted with asymmetric membranes from different sides of the bilayer, thus mimicking different dendrimer transport stages. The G4 dendrimer could insert into the membrane during an equilibrated state, and the G5 dendrimer could induce pore formation in the membrane when the dendrimers interacted with the outer side (outer interactions) of an asymmetric membrane [with 10% dipalmitoyl phosphatidylserine (DPPS) in the inner leaflet of the membrane]. During the interaction with the inner side of the asymmetric membrane (inner interactions), the G4 and G5 dendrimers only adsorbed onto the membrane. As the membrane asymmetry increased (e.g., increased DPPS percentage in the inner leaflet of the membrane), the G4 and G5 dendrimers penetrated deeper into the membrane during the outer interactions and the G4 and G5 dendrimers were adsorbed more tightly onto the membrane for the inner interactions. When the DPPS content reached 50%, the G4 dendrimer could completely penetrate through the membrane from the outer side to the inner side. Our study provides molecular understanding and reference information about different dendrimer transport stages during drug and gene delivery.

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“…10,12,27 In addition, the degree of membrane disruption parallels the degree of nonselective tissue uptake observed in vivo. 29 This correlation between the AFM/SLB assays and the in vitro and in vivo studies inspired us to examine the disruption between other nanoparticles that are well precedented to disrupt and/or translocate across cell membranes.…”

mentioning

confidence: 92%

Wide Varieties of Cationic Nanoparticles Induce Defects in Supported Lipid Bilayers

et al. 2008

Self Cite

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Nanoparticles with widely varying physical properties and origins (spherical versus irregular, synthetic versus biological, organic versus inorganic, flexible versus rigid, small versus large) have been previously noted to translocate across the cell plasma membrane. We have employed atomic force microscopy to determine if the physical disruption of lipid membranes, formation of holes and/or thinned regions, is a common mechanism of interaction between these nanoparticles and lipids. It was found that a wide variety of nanoparticles, including a cell penetrating pepide (MSI-78), a protein (TAT), polycationic polymers (PAMAM dendrimers, pentanol-core PAMAM dendrons, polyethyleneimine, and diethylaminoethyl-dextran), and two inorganic particles (Au-NH 2, SiO 2 -NH 2 ), can induce disruption, including the formation of holes, membrane thinning, and/or membrane erosion, in supported lipid bilayers.

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Interaction of Poly(amidoamine) Dendrimers with Supported Lipid Bilayers and Cells: Hole Formation and the Relation to Transport

Cited by 574 publications

References 24 publications

Surface-structure-regulated cell-membrane penetration by monolayer-protected nanoparticles

Surface-structure-regulated cell-membrane penetration by monolayer-protected nanoparticles

Molecular analysis of interactions between dendrimers and asymmetric membranes at different transport stages

Wide Varieties of Cationic Nanoparticles Induce Defects in Supported Lipid Bilayers

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