Membrane solubilization by a hydrophobic polyelectrolyte: surface activity and membrane binding

Thomas, James L.; Barton, Scott W.; Tirrell, David A.

doi:10.1016/s0006-3495(94)80575-2

Cited by 74 publications

(69 citation statements)

References 7 publications

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“…With increasing the concentration of the adsorbed PP75 to 5.8 μM, the virus-mimicking liposomes displayed a high level of relative hemolysis at 71.9 ± 3.1 % at pH 7.4. This is consistent with the report that a sufficiently high concentration of poly(α-ethylacrylic acid) may lead to complete membrane destabilization 45 . With acidification to pH ≤5.0, the PP75-coated, virusmimicking liposomes lost their hemolytic activity as a result of the formation of liposomal aggregates ( Figure 4A).…”

Section: Cell Membrane Destabilizationsupporting

confidence: 93%

A Virus-Mimicking, Endosomolytic Liposomal System for Efficient, pH-Triggered Intracellular Drug Delivery

Chen

2016

ACS Appl. Mater. Interfaces

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A novel multifunctional liposomal delivery platform has been developed to resemble the structural and functional traits of an influenza virus. Novel pseudo-peptides were prepared to mimic the pHresponsive endosomolytic behavior of influenza viral peptides through grafting a hydrophobic amino acid, L-phenylalanine, onto the backbone of a polyamide, poly(L-lysine isophthalamide), at various degrees of substitution. These pseudo-peptidic polymers were employed to functionalize the surface of cholesterol-containing liposomes that mimic the viral envelope. By controlling the cholesterol proportion, as well as the concentration and amphiphilicity of the pseudo-peptides, the entire payload was rapidly released at endosomal pHs whilst there was no release at pH 7.4. A pH-triggered, reversible change in liposomal size was observed and the release mechanism was elucidated. In addition, the virus-mimicking nanostructures efficiently disrupted the erythrocyte membrane at pH 6.5 characteristic of early endosomes, whilst showed negligible cytotoxic effects at physiological pH. The efficient intracellular delivery of the widely used anticancer drug doxorubicin (DOX) by the multifunctional liposomes was demonstrated, leading to significantly increased potency against HeLa cancer cells over the DOX-loaded bare liposomes. This novel virus-mimicking liposomal system, with the incorporated synergy of efficient liposomal drug release and efficient endosomal escape, is favorable for efficient intracellular drug delivery.3

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Section: Cell Membrane Destabilizationsupporting

confidence: 93%

A Virus-Mimicking, Endosomolytic Liposomal System for Efficient, pH-Triggered Intracellular Drug Delivery

Chen

2016

ACS Appl. Mater. Interfaces

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“…Our results show that the hemolytic activity of all the compounds was strongly influenced by concentration. Likewise, several authors [18,32,33] have reported similar results for the membrane-lytic activity of the polymers poly(α-ethylacrylic acid) and poly( L -lysine iso-phthalamide), and for arginine-based gemini surfactants, respectively. In the case of polymers, those authors argued that increasing compound concentration enhances the migration of the polymer molecules to lipid bilayer membranes, thereby resulting in an increase in the membrane destabilization.…”

Section: Concentration-dependent Hemolysismentioning

confidence: 52%

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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“…Their surface tensiometry results were consistent with a micellization process driven by hydrophobic interactions of the polymer and the lipid bilayer. Such a mechanism is similar to that seen for amphiphilic, R-helix-based polypeptides, but the polymer is unlikely to adopt a secondary structure, implying that the hydrophobic-to-hydrophilic ratio is the most important factor in liposome micellization (15). They also found that the rate of micellization was determined by the rate and extent of PEAAc absorption, which in turn was determined by the lateral compressibility of the membrane (16).…”

Section: Discussionmentioning

confidence: 69%

“…We have not investigated the mechanism of this action, but Tirrell and co-workers have studied the disruption of liposomes by PEAAc (15). Their surface tensiometry results were consistent with a micellization process driven by hydrophobic interactions of the polymer and the lipid bilayer.…”

Section: Discussionmentioning

confidence: 92%

Hemolytic Activity of pH-Responsive Polymer-Streptavidin Bioconjugates

et al. 1999

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Drug delivery systems that increase the rate and/or quantity of drug release to the cytoplasm are needed to enhance cytosolic delivery and to circumvent nonproductive cell trafficking routes. We have previously demonstrated that poly(2-ethylacrylic acid) (PEAAc) has pH-dependent hemolytic properties, and more recently, we have found that poly(2-propylacrylic acid) (PPAAc) displays even greater pHresponsive hemolytic activity than PEAAc at the acidic pHs of the early endosome. Thus, these polymers could potentially serve as endosomal releasing agents in immunotoxin therapies. In this paper, we have investigated whether the pH-dependent membrane disruptive activity of PPAAc is retained after binding to a protein. We did this by measuring the hemolytic activity of PPAAc-streptavidin model complexes with different protein to polymer stoichiometries. Biotin was conjugated to amine-terminated PPAAc, which was subsequently bound to streptavidin by biotin complexation. The ability of these samples to disrupt red blood cell membranes was investigated for a range of polymer concentrations, a range of pH values, and two polymer-to-streptavidin ratios of 3:1 and 1:1. The results demonstrate that (a) the PPAAc-streptavidin complex retains the ability to lyse the RBC lipid bilayers at low pHs, such as those existing in endosomes, and (b) the hemolytic ability of the PPAAc-streptavidin complex is similar to that of the free PPAAc.

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Membrane solubilization by a hydrophobic polyelectrolyte: surface activity and membrane binding

Cited by 74 publications

References 7 publications

A Virus-Mimicking, Endosomolytic Liposomal System for Efficient, pH-Triggered Intracellular Drug Delivery

A Virus-Mimicking, Endosomolytic Liposomal System for Efficient, pH-Triggered Intracellular Drug Delivery

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

Hemolytic Activity of pH-Responsive Polymer-Streptavidin Bioconjugates

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