Multiple poloxamers increase plasma membrane repair capacity in muscle and nonmuscle cells

Abstract

Various previous studies established that the amphiphilic tri-block copolymer known as poloxamer 188 (P188) or Pluronic-F68 can stabilize the plasma membrane following a variety of injuries to multiple mammalian cell types. This characteristic led to proposals for the use of P188 as a therapeutic treatment for various disease states, including muscular dystrophy. Previous studies suggest that P188 increases plasma membrane integrity by resealing plasma membrane disruptions through its affinity for the hydrophobic lipid chains on the lipid bilayer. P188 is one of a large family of copolymers that share the same basic tri-block structure consisting of a middle hydrophobic propylene oxide segment flanked by two hydrophilic ethylene oxide moieties [poly(ethylene oxide)80-poly(propylene oxide)27-poly(ethylene oxide)80]. Despite the similarities of P188 to the other poloxamers in this chemical family, there has been little investigation into the membrane-resealing properties of these other poloxamers. In this study we assessed the resealing properties of poloxamers P181, P124, P182, P234, P108, P407, and P338 on human embryonic kidney 293 (HEK293) cells and isolated muscle from the mdx mouse model of Duchenne muscular dystrophy. Cell membrane injuries from glass bead wounding and multiphoton laser injury show that the majority of poloxamers in our panel improved the plasma membrane resealing of both HEK293 cells and dystrophic muscle fibers. These findings indicate that many tri-block copolymers share characteristics that can increase plasma membrane resealing and that identification of these shared characteristics could help guide design of future therapeutic approaches.

Poloxamer 188 Exerts Direct Protective Effects on Mouse Brain Microvascular Endothelial Cells in an In Vitro Traumatic Brain Injury Model

“…Biomedicines 2021, 9, 1043 2 of 32 Poloxamer 188 (P188), a non-toxic, nonionic linear synthetic triblock copolymer, is built of a hydrophobic polypropylene oxide center bordered by two hydrophilic polyethylene oxide chains [10][11][12]. P188 displayed protective effects against I/R injury as well as against injury following TBI in multiple in vitro models [13][14][15][16][17][18][19][20][21].…”

Poloxamer 188 Protects Isolated Adult Mouse Cardiomyocytes from Reoxygenation Injury

“…CCMS, or Poloxamers, are synthetic non‐ionic block copolymer molecules available in varying molecular weights (MW) and ratios of hydrophobic polypropylene oxide (PPO) to hydrophilic polyethylene oxide (PEO) chains. Poloxamer 188 (P188) is a flexible tri‐block CCMS composed of single bonds and a central hydrophobic 30 PPO unit chain that covalently connects two hydrophilic 75 PEO unit chains (Figure 1A), making P188 ~ 20% hydrophobic with an average MW of 8400 g/mol 14,15 . Through work using X‐ray scattering, atomic force microscopy, and computer simulations, it is thought that P188 directly seals and stabilizes cell membranes by inserting the hydrophobic portion into damaged areas of the membrane while the hydrophilic chains interact with the lipid headgroups of the bilayer and remain at the surface of the membrane, ultimately closing the tear 16‐18 …”

“…Poloxamer 188 (P188) is a flexible tri-block CCMS composed of single bonds and a central hydrophobic 30 PPO unit chain that covalently connects two hydrophilic 75 PEO unit chains (Figure 1A), making P188 ~20% hydrophobic with an average MW of 8400 g/mol. 14,15 Through work using X-ray scattering, atomic force microscopy, and computer simulations, it is thought that P188 directly seals and stabilizes cell membranes by inserting the hydrophobic portion into damaged areas of the membrane while the hydrophilic chains interact with the lipid headgroups of the bilayer and remain at the surface of the membrane, ultimately closing the tear. [16][17][18] Thus, our study was based on the hypothesis that P188, with its unique hydrophobic/hydrophilic chemical properties, and given only on reoxygenation, can protect cardiomyocytes against further injury from reoxygenation following hypoxia by stabilizing the damaged cell membrane, and allowing remaining viable cells to maintain function.…”

Electrophysiological analysis of healthy and dystrophic 3D bioengineered skeletal muscle tissues

“…Using block copolymers such as poloxamer188 (P188) have also been shown to protect dystrophic muscles from mechanical stress by stabilizing the phospholipid plasma membrane (Houang et al, 2015). Though various studies have established that P188, an amphiphilic block copolymer, can stabilize the plasma membrane and increase membrane integrity by resealing disruptions of the plasma membrane, these studies have only been conducted in mdx mice and human embryonic kidney cells (Andrews and Corrotte, 2018; Bansal et al, 2003; Moloughney and Weisleder, 2012; Kwiatkowski et al, 2020). Since it is known that the membrane of DMD muscles is damaged, we sought out to test the ability of P188 to improve membrane fragility of DMD muscle cells.…”