Effects of PEO−PPO−PEO Triblock Copolymers on Phospholipid Membrane Integrity under Osmotic Stress

Wang, Jiayu; Chin, Jaemin; Marks, Jeremy D.; Lee, Ka Yee C.

doi:10.1021/la101841a

Cited by 57 publications

(101 citation statements)

References 51 publications

(74 reference statements)

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“…Polymers in the hairpin state, on the other hand, have only minor impact on the membrane permeability. This supports the hypothesis of a two state model for the effect of such polymers on bilayer membranes as suggested by Wang et al, 18 with an "insertion state" leading to an increased permeability, and an "adsorption state", which does not have this effect ( Figure 10). …”

Section: Discussionsupporting

confidence: 88%

Interactions of Amphiphilic Triblock Copolymers with Lipid Membranes: Modes of Interaction and Effect on Permeability Examined by Generic Monte Carlo Simulations

2015

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We investigate interactions of linear amphiphilic ABA triblock copolymers with lipid bilayer membranes by means of Monte Carlo simulations in a generic coarse-grained model. The polymers have hydrophilic A-blocks and B-blocks of varying hydrophobicity. The effect of different conformational states of the polymer on the induced permeability for solvent molecules is examined. We demonstrate that the local permeability of the membrane can be strongly increased in the transmembrane state, in particular for a mismatch in the hydrophobicity between the middle block and the membrane core, while the hairpin state has almost no effect on this property, especially for growing hydrophobic mismatch. We have investigated the relative stability of the two states using thermodynamic integration and have shown that only in a range of intermediate hydrophobic block lengths N B and hydrophobicities H B the transmembrane state is stable. Increasing mismatch of the B-block in terms of relative hydrophobicity and block length not only causes stronger perturbations in the membrane if the polymer is in the transmembane state but also renders this state metastable. Our studies support in particular previous experimental studies suggesting a two-state model of PEO−PPO−PEO copolymers.

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Section: Discussionsupporting

confidence: 88%

Interactions of Amphiphilic Triblock Copolymers with Lipid Membranes: Modes of Interaction and Effect on Permeability Examined by Generic Monte Carlo Simulations

2015

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“…Depending on the length of the PPO and PEO blocks they show very different behaviour. On the one hand they have been shown to disturb the membrane integrity leading to an increased permeability and facilitated translocation of dyes 1 or drugs 2 across the membrane; on the other hand they can also act as membrane sealants, which reduce membrane leakage or even help to restore the permeation barrier of damaged membranes.…”

Section: Introductionmentioning

confidence: 99%

Binding of amphiphilic and triphilic block copolymers to lipid model membranes: the role of perfluorinated moieties

et al. 2014

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A novel class of symmetric amphi-and triphilic (hydrophilic, lipophilic, fluorophilic) block copolymers has been investigated with respect to their interactions with lipid membranes. The amphiphilic triblock copolymer has the structure PGMA 20 -PPO 34 -PGMA 20 (GP) and it becomes triphilic after attaching perfluoroalkyl moieties (F9) to either end which leads to F 9 -PGMA 20 -PPO 34 -PGMA 20 -F 9 (F-GP). The hydrophobic poly(propylene oxide) (PPO) block is sufficiently long to span a lipid bilayer. The poly(glycerol monomethacrylate) (PGMA) blocks have a high propensity for hydrogen bonding. The hydrophobic and lipophobic perfluoroalkyl moieties have the tendency to phase segregate in aqueous as well as in hydrocarbon environments. We performed differential scanning calorimetry (DSC) measurements on polymer bound lipid vesicles under systematic variation of the bilayer thickness, the nature of the lipid headgroup, and the polymer concentration. The vesicles were composed of phosphatidylcholines (DMPC, DPPC, DAPC, DSPC) or phosphatidylethanolamines (DMPE, DPPE, POPE). We showed that GP as well as F-GP binding have membrane stabilizing and destabilizing components.PPO and F9 blocks insert into the hydrophobic part of the membrane concomitantly with PGMA block adsorption to the lipid headgroup layer. The F9 chains act as additional membrane anchors. The insertion of the PPO blocks of both GP and F-GP could be proven by 2D-NOESY NMR spectroscopy. By fluorescence microscopy we show that F-GP binding increases the porosity of POPC giant unilamellar vesicles (GUVs), allowing the influx of water soluble dyes as well as the translocation of the complete triphilic polymer and its accumulation at the GUV surface. These results open a new route for the rational design of membrane systems with specific properties.

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“…To directly determine the interaction of F-68 with the plasma membrane, we employed fluorescent dye-loaded GUVs, (made up of POPC, POPG, Biotin-PE, and Texas Rd-tagged DHPE in 88/10/1/1 mol ratio) as a highly-reduced model of the plasma membrane, and induced loss of membrane integrity with hypo-osmotic stress (Wang et al, 2010). When incubated in hypo-osmolar solutions, GUVs initially swelled elastically, and then demonstrated dye leakage through membrane pores induced by decreased lipid packing density in response to swelling.…”

Section: Pluronic-mediated Cellular Rescue From Injury: State Of Tmentioning

confidence: 99%

“…When incubated in hypo-osmolar solutions, GUVs initially swelled elastically, and then demonstrated dye leakage through membrane pores induced by decreased lipid packing density in response to swelling. In the presence of F-68 (50 μm), the period of elastic swelling was increased (Wang et al, 2010). However, F-68 failed to block or significantly inhibit dye leakage (Wang et al, 2010), suggesting that a simple model of plasma membrane sealing is inadequate to explain the neuronal rescue properties of F-68.…”

Section: Pluronic-mediated Cellular Rescue From Injury: State Of Tmentioning

confidence: 99%

“…In the presence of F-68 (50 μm), the period of elastic swelling was increased (Wang et al, 2010). However, F-68 failed to block or significantly inhibit dye leakage (Wang et al, 2010), suggesting that a simple model of plasma membrane sealing is inadequate to explain the neuronal rescue properties of F-68.…”

Section: Pluronic-mediated Cellular Rescue From Injury: State Of Tmentioning

confidence: 99%

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Mitochondrial mechanisms of neuronal rescue by F-68, a hydrophilic Pluronic block co-polymer, following acute substrate deprivation

Wang

Bindokas

Skinner

et al. 2017

Neurochemistry International

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Global brain ischemia can lead to widespread neuronal death and poor neurologic outcomes in patients. Despite detailed understanding of the cellular and molecular mechanisms mediating neuronal death following focal and global brain hypoxia-ischemia, treatments to reduce ischemia-induced brain injury remain elusive. One pathway central to neuronal death following global brain ischemia is mitochondrial dysfunction, one consequence of which is the cascade of intracellular events leading to mitochondrial outer membrane permeabilization. A novel approach to rescuing injured neurons from death involves targeting cellular membranes using a class of synthetic molecules called Pluronics. Pluronics are triblock copolymers of hydrophilic poly[ethylene oxide] (PEO) and hydrophobic poly[propylene oxide] (PPO). Evidence is accumulating to suggest that hydrophilic Pluronics rescue injured neurons from death following substrate deprivation by preventing mitochondrial dysfunction. Here, we will review current understanding of the nature of interaction of Pluronic molecules with biological membranes and the efficacy of F-68, an 80% hydrophilic Pluronic, in rescuing neurons from injury. We will review data indicating that F-68 reduces mitochondrial dysfunction and mitochondria-dependent death pathways in a model of neuronal injury in vitro, and present new evidence that F-68 acts directly on mitochondria to inhibit mitochondrial outer membrane permeabilization. Finally, we will present results of a pilot, proof-of-principle study suggesting that F-68 is effective in reducing hippocampal injury induced by transient global ischemia in vivo. By targeting mitochondrial dysfunction, F-68 and other Pluronic molecules constitute an exciting new approach to rescuing neurons from acute injury.

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Effects of PEO−PPO−PEO Triblock Copolymers on Phospholipid Membrane Integrity under Osmotic Stress

Cited by 57 publications

References 51 publications

Interactions of Amphiphilic Triblock Copolymers with Lipid Membranes: Modes of Interaction and Effect on Permeability Examined by Generic Monte Carlo Simulations

Interactions of Amphiphilic Triblock Copolymers with Lipid Membranes: Modes of Interaction and Effect on Permeability Examined by Generic Monte Carlo Simulations

Binding of amphiphilic and triphilic block copolymers to lipid model membranes: the role of perfluorinated moieties

Mitochondrial mechanisms of neuronal rescue by F-68, a hydrophilic Pluronic block co-polymer, following acute substrate deprivation

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