Characterization of Conformation and Interaction of Gene Delivery Vector Polyethylenimine with Phospholipid Bilayer at Different Protonation State

Choudhury, C.; Kumar, Abhinaw; Roy, Sudip

doi:10.1021/bm4011408

Cited by 39 publications

(47 citation statements)

References 50 publications

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“…Endosomal leakiness can be a result of small defects that arise in the endosomal membrane when pressure builds up upon osmotic swelling in combination with interaction of the protonated PEI chains with the endosomal lipid biliayer. 55 Co-incubation of PEI polyplexes with quenched calcein confirmed this hypothesis since both HeLa and ARPE-19 cells that had taken up PEI/pDNA polyplexes showed cytosolic calcein release in virtually every cell whereas calcein remained trapped in endosomes in the absence of polyplexes (Fig. 7).…”

Section: Endosomal Leakinesssupporting

confidence: 54%

Endosomal Size and Membrane Leakiness Influence Proton Sponge-Based Rupture of Endosomal Vesicles

et al. 2018

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In gene therapy, endosomal escape represents a major bottleneck since nanoparticles often remain entrapped inside endosomes and are trafficked toward the lysosomes for degradation. A detailed understanding of the endosomal barrier would be beneficial for developing rational strategies to improve transfection and endosomal escape. By visualizing individual endosomal escape events in live cells, we obtain insight into mechanistic factors that influence proton sponge-based endosomal escape. In a comparative study, we found that HeLa cells treated with JetPEI/pDNA polyplexes have a 3.5-fold increased endosomal escape frequency compared to ARPE-19 cells. We found that endosomal size has a major impact on the escape capacity. The smaller HeLa endosomes are more easily ruptured by the proton sponge effect than the larger ARPE-19 endosomes, a finding supported by a mathematical model based on the underlying physical principles. Still, it remains intriguing that even in the small HeLa endosomes, <10% of the polyplex-containing endosomes show endosomal escape. Further experiments revealed that the membrane of polyplex-containing endosomes becomes leaky to small compounds, preventing effective buildup of osmotic pressure, which in turn prevents endosomal rupture. Analysis of H1299 and A549 cells revealed that endosomal size determines endosomal escape efficiency when cells have comparable membrane leakiness. However, at high levels of membrane leakiness, buildup of osmotic pressure is no longer possible, regardless of endosomal size. Based on our findings that both endosomal size and membrane leakiness have a high impact on proton sponge-based endosomal rupture, we provide important clues toward further improvement of this escape strategy.

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Section: Endosomal Leakinesssupporting

confidence: 54%

Endosomal Size and Membrane Leakiness Influence Proton Sponge-Based Rupture of Endosomal Vesicles

et al. 2018

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“…Simulations showed that individual cationic oligomers can bind the lipid bilayer surface, driven by the electrostatic interactions with the lipid phosphate groups. Occasionally an oligomer inserted more deeply in the membrane, as observed for PEI [92], without destabilizing membrane structure. Simultaneous interaction of two oligomers, instead, led to the formation water pores.…”

Section: Linear Polyelectrolitesmentioning

confidence: 89%

“…Its protonation state is controlled simply by pH, and the protonated form (low pH) is known to be cytotoxic [91]. Choudhury et al studied the interaction of linear PEI with zwitterionic (POPC) membranes using atomistic MD simulations [92]. In simulations, both the protonated form (extended) and the unprotonated form (compact) interacted stably with the membrane surface, without affecting membrane structural properties.…”

Section: Linear Polyelectrolitesmentioning

confidence: 99%

Simulating the interaction of lipid membranes with polymer and ligand-coated nanoparticles

Rossi

Monticelli

2016

Advances in Physics: X

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Nanoscience and nanotechnology are undergoing rapid expansion owing to the promise of breakthroughs in key sectors, such as energy and medicine. As for medicine, interaction of nanomaterials with biological membranes is a key issue, both for the development of drug and gene delivery vectors and for understanding the molecular basis of nanoparticle (NP) biological activity. NP-membrane interactions are often studied with the aid of molecular simulations of model membranes, allowing to overcome the limitations in temporal and spatial resolution generally encountered by experimental techniques applied to fluid membranes. In the present review we summarize the current literature on simulations of NP-membrane interactions, focusing on small polymeric and ligand-coated NPs. Open questions emerging from experiments concern the effect of NP size, surface charge, and ligand arrangement on NP partitioning into and permeation across membranes. While simulations are contributing to significant progress in this area, some challenges remain, namely regarding the representation of the complexity of biological environments and the cooperative behavior of NPs (e.g. aggregation), as well as methodological challenges to tackle the intrinsically multi-scale nature of nano-bio interactions.

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“…The mechanism by which polymers modify and interact with lipid bilayers is a crucial step for the development of new polymer-based drug nano-carriers. [1][2][3][4] Such nanocarriers can be developed entirely from polymers (polymersomes, micelles, dendrimers), 5 or, to minimize the side effects, be self-assembled from a mixture of polymers and lipids (hybrid particles). The latter type of vesicles should have the advantage of retaining the good mechanical properties typical of the polymer vesicles and of displaying milder adverse effects.…”

Section: Introductionmentioning

confidence: 99%

How the Incorporation of Pluronic Block Copolymers Modulates the Response of Lipid Membranes to Mechanical Stress

Zaki

Carbone

2017

Langmuir

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We employ atomistic molecular dynamics simulations to investigate the effect that the incorporation of the nonionic amphiphilic copolymer known as Pluronic L64 has on the mechanical stability of a DPPC membrane. The simulations reveal that the incorporation of the polymer chains leads to membranes that can sustain increasing mechanical stresses. Analysis of mechanical, structural, and dynamic properties of the membrane shows that the polymer chains interact strongly with the lipids in the vicinity, restraining their mobility and imparting better mechanical stability to the membrane. The hybrid membranes under tension remain thicker, more ordered, and stiffer in comparison to their lipid analogues. Trans-bilayer lipid movements (flip-flop) are observed and appear to be triggered by the presence of the polymer chains. A careful analysis of the pore formation under high tensions reveals two distinctive mechanisms that depend on the distribution of the hydrophilic polymer blocks in the bilayer. Finally, the rate of growth of the formed membrane defects is slowed down in the presence of polymers. These findings show that Pluronic block copolymers could be exploited for the formation of optimized hybrid nanodevices with controlled elastic and dynamic properties.

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Characterization of Conformation and Interaction of Gene Delivery Vector Polyethylenimine with Phospholipid Bilayer at Different Protonation State

Cited by 39 publications

References 50 publications

Endosomal Size and Membrane Leakiness Influence Proton Sponge-Based Rupture of Endosomal Vesicles

Endosomal Size and Membrane Leakiness Influence Proton Sponge-Based Rupture of Endosomal Vesicles

Simulating the interaction of lipid membranes with polymer and ligand-coated nanoparticles

How the Incorporation of Pluronic Block Copolymers Modulates the Response of Lipid Membranes to Mechanical Stress

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