Development of Biocompatible Polymers for Modulating Lipid Membrane Integrity

The cell membrane is in essence an integral lipid bilayer decorated by proteins and carbohydrates. It separates the interior of a cell from the exterior environment and serves as a permeable barrier by control over the passage of large molecules and ions in and out of the cell. Thus, lipid membrane integrity is essential for the function of the cell. Research studies have shown that a family of PEO-PPO-PEO triblock copolymers, also known as poloxamers, actively interact with lipid membranes but can have opposite effects on membrane integrity - depending on their architecture, they can behave either as membrane sealants in the sealing of injured cell membranes or as permeabilizers to promote drug intake for multidrug-resistant cancer cells. It is intriguing that these seemingly opposite biological effects can come from the interaction between biological cell membranes and the same family of triblock copolymers. However, no clear relationship between architectures and biomedical functionality of the copolymers has been established due to the lack of thorough understanding of the mechanism behind poloxamer-cell membrane interactions at the molecular level. In this work, we elucidate the origin of the poloxamer’s biomedical functionality by investigating interactions between PEO-PPO-PEO triblock copolymers and lipid membranes using a suite of biophysical techniques. Our results indicate that the overall hydrophobicity of the triblock copolymer plays an important role in determining its ability to disrupt or preserve the integrity of lipid membranes. To test the universal effect of polymer hydrophobicity, we have further examined polymer-lipid membrane interactions using a new series of poloxamer-mimetic triblock copolymers, PMPC-PPO-PMPC. We discovered that this family of copolymers exhibits a similar interaction trend to poloxamers. As PMPC does not share any common chemical feature with PEO except that it is also highly hydrophilic - in fact, it is much more hydrophilic than PEO, we propose that it is the overall hydrophobicity of the polymer, rather than the exact chemical structure of both blocks, drives the transition of the polymer from being a membrane permeabilizer to a membrane sealant. Insights gained from this study should aid the design and development of novel copolymers as therapeutics.