pH-responsive pseudo-peptides for cell membrane disruption

Eccleston, Mark E.; Kuiper, Marcel; Gilchrist, Fiona M.; Slater, Nigel K.H.

doi:10.1016/s0168-3659(00)00316-3

Cited by 51 publications

(44 citation statements)

References 20 publications

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“…33 The electrostatic repulsion between the anionic polymers and the negatively charged cell membrane could prevent the effective membrane binding and insertion of the polymers. Although the linear parent polymer PLP displayed a coil-to-globule conformational change at acidic pH 22 , no or low hemolysis was observed for PLP at 0.5 mg mL -1 within the pH range tested (from pH 7.4 to 4.5) due to the 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 limited polymer-membrane interaction. For the comb-like PLP-NDA polymers bearing hydrophobic relatively long side chains, the largely increased hydrophobic interaction could overweigh the electrostatic repulsion.…”

Section: Mechanism Of Cell Membrane Disruptionmentioning

confidence: 99%

“…21 The amphiphilic pseudopeptide does not contain long aliphatic chains that are present in many membrane proteins, and displays low cell membrane disruptive capacity only at relatively low pH (4.5-5.0), which is outside the endosomal pH range. 22 Herein, we report a series of comb-like polymers synthesized by grafting hydrophobic decylamine (NDA) onto the carboxylic acid groups along the PLP backbone at different densities. The effects of the conjugated relatively long chains on the pH-responsiveness of polymer conformation and membrane destabilization were investigated.…”

Section: Introductionmentioning

confidence: 99%

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Membrane-Anchoring, Comb-Like Pseudopeptides for Efficient, pH-Mediated Membrane Destabilization and Intracellular Delivery

Chen

Wang

Kopytynski

et al. 2017

ACS Appl. Mater. Interfaces

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Endosomal release has been identified as a rate-limiting step for intracellular delivery of therapeutic agents, in particular macromolecular drugs. Herein, we report a series of synthetic pH-responsive, membrane-anchoring polymers exhibiting dramatic endosomolytic activity for efficient intracellular delivery. The comb-like pseudopeptidic polymers were synthesized by grafting different amounts of decylamine (NDA), which act as hydrophobic membrane anchors, onto the pendant carboxylic acid groups of a pseudopeptide, poly (L-lysine isophthalamide). The effects of the hydrophobic relatively long alkyl side chains on aqueous solution properties, cell membrane destabilization activity and in-vitro cytotoxicity were investigated. The optimal polymer containing 18 mol% NDA exhibited limited hemolysis at pH 7.4, but induced nearly complete membrane destabilization at endosomal pH within only 20 min. The mechanistic investigation of membrane destabilization suggests the polymermediated pore formation. It has been demonstrated that the polymer with hydrophobic side chains displayed a considerable endosomolytic ability to release endocytosed materials into the cytoplasm of various cell lines, which is of critical importance for intracellular drug delivery applications.

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Section: Mechanism Of Cell Membrane Disruptionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Membrane-Anchoring, Comb-Like Pseudopeptides for Efficient, pH-Mediated Membrane Destabilization and Intracellular Delivery

Chen

Wang

Kopytynski

et al. 2017

ACS Appl. Mater. Interfaces

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“…Moreover, cationic amino acid-based surfactants have been used to prepare novel biocompatible devices for the controlled encapsulation and release of DNA [11]. Cationic and anionic polymers with pH-sensitive activity, including nonbiodegradable polymers and biodegradable poly(amino acid)s and pseudo-peptides [2,7,[12][13][14][15][16][17][18], have also been developed to promote endosomal escape. Cationic compounds have commonly been used to form stable cationic complexes; however, they show cytotoxicity and non-specifically adsorb serum proteins, thereby leading to rapid blood clearance as a result of the strong cationic surface charge [19][20][21].…”

Section: Introductionmentioning

confidence: 99%

The role of counterions in the membrane-disruptive properties of pH-sensitive lysine-based surfactants

et al. 2011

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Surfactants are among the most versatile and widely used excipients in pharmaceuticals.This versatility, together with their pH-responsive membrane-disruptive activity and low toxicity, could also enable their potential application in drug delivery systems. Here we studied five anionic lysine-based surfactants that differ in the nature of their counterion.We examined their capacity to disrupt the cell membrane under a range of pH values, concentrations and incubation times using a standard hemolysis assay as a model for endosomal membranes. The surfactants showed pH-sensitive hemolytic activity and improved kinetics at the endosomal pH range. Low concentrations resulted in negligible hemolysis at physiological pH and high membrane lytic activity at pH 5.4, which is in the range characteristic of late endosomes. With increasing concentration, the surfactants showed an enhanced capacity to lyse cell membranes, and also caused significant membrane disruption at physiological pH. This observation indicates that at high concentrations surfactant behavior is independent of pH. We addressed the mechanism of surfactant-mediated membrane destabilization, and also performed scanning electron microscopy studies to evaluate the effects of the compounds on erythrocyte morphology as a function of pH. The in vitro cytotoxicity of the surfactants was assessed by MTT and NRU assays with the 3T3 cell line. The influence of different types of counterion on hemolytic activity and the potential applications of these surfactants in drug delivery are discussed. The possibility of using pH-sensitive surfactants for endosome disruption could hold great promise for intracellular drug delivery systems in future therapeutic applications.

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“…To survive long-term storage at low temperatures, cells require treatment with cryoprotective agents, such as dimethyl sulfoxide (Me 2 SO) or glycerol [7][8][9], the toxicity of which has been recognized as a critical barrier to further advancement of the field [7,10]. Sugars are key non-toxic components in many cryopreservation protocols yet transmembrane transport of sugars is restricted to monosaccharides since disaccharides do not readily diffuse across the plasma membrane [11].…”

Section: Introductionmentioning

confidence: 99%

“…Sugars are key non-toxic components in many cryopreservation protocols yet transmembrane transport of sugars is restricted to monosaccharides since disaccharides do not readily diffuse across the plasma membrane [11]. This is a major challenge when high concentrations of disaccharides such as trehalose are needed within cells for viable cryopreservation [7,12]. Approaches have been developed to increase the levels of intracellular disaccharides, such as the use of ATP receptor channels or engineered membrane pores [12][13][14].…”

Section: Introductionmentioning

confidence: 99%

Antioxidant modified amphiphilic polymer improves intracellular cryoprotectant delivery and alleviates oxidative stress in HeLa cells

Chen¹,

Mercado²,

Slater³

2017

Adv Mater Sci

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The design and synthesis of a dual-function, cell permeating polymer with an antioxidative property is described and its use for the intracellular delivery of the cryoprotectant trehalose into HeLa cells is demonstrated. The polymer, PVitE-25, was created by grafting the water insoluble hydrophobic antioxidant (±)-α-Tocopherol (vitamin E) onto pendant carboxylate groups of a biocompatible cell permeating polymer, poly (L-lysine iso-phthalamide) (PLP). The modification increased the intracellular delivery efficiency of the polymer and also introduced an antioxidative effect that was able to reduce 85% of reactive oxygen species (ROS) in HeLa cells incubated with 1 mM hydrogen peroxide (H 2 O 2 ), as determined by 2′,7′-Dichlorofluorescin diacetate (DCFH-DA) probe. PVitE-25 was also used to load the cropreservative trehalose into HeLa cells prior to freezing such that the level of cell viability measured 48 hours after cell revival was comparable to that observed with a standard Me 2 SO-based cryopreservation protocol. This is the first report of a synthetic intracellular delivery system that facilitates the intracellular delivery of the cryoprotectant, trehalose, and mitigates oxidative stress during the freeze thaw cycle of cryopreservation.

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pH-responsive pseudo-peptides for cell membrane disruption

Cited by 51 publications

References 20 publications

Membrane-Anchoring, Comb-Like Pseudopeptides for Efficient, pH-Mediated Membrane Destabilization and Intracellular Delivery

Membrane-Anchoring, Comb-Like Pseudopeptides for Efficient, pH-Mediated Membrane Destabilization and Intracellular Delivery

The role of counterions in the membrane-disruptive properties of pH-sensitive lysine-based surfactants

Antioxidant modified amphiphilic polymer improves intracellular cryoprotectant delivery and alleviates oxidative stress in HeLa cells

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