Interaction between human serum albumin and cholesterol-grafted polyglutamate as the potential carriers of protein drugs

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Abstract

Currently there is no successful platform technology for the sustained release of protein drugs. It seems inevitable to specifically develop new materials for such purpose, and hence the understanding of protein–material interactions is highly desirable. In this study, we synthesized cholesterol-grafted polyglutamate (PGA-g-Chol) as a hydrophobically-modified polypeptide, and thoroughly characterized its interaction with a model protein (human serum albumin) in the aqueous solution by using circular dichroism, fluorescence methods, and light scattering. With the protein concentration fixed at 5 μmol/L, adding PGA-g-Chol polymers into the solution resulted in continuous blue shift of the protein fluorescence (from 339 to 332 nm), until the polymer molar concentration reached the same value as the protein. In contrast, the un-modified polyglutamate polymers apparently neither affected the protein microenvironment nor formed aggregates. Based on the experimental data, we proposed a physical picture for such protein–polymer systems, where the polymer first bind with the protein in a 1:1 molar ratio via a fraction of their hydrophobic pendant cholesterol resides along the polymer chain. In this protein/polymer complex, there are excess unbound cholesterol residues. As the polymer concentration increases, the polymers form multi-polymer aggregates around 200 nm in diameter via the same hydrophobic cholesterol residues. The protein/polymer complex also participate in the aggregation via their excess cholesterol residues, and consequently the proteins are encapsulated into the nanoparticles. The encapsulation was also found to increase the thermal stability of the model protein.

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Lyu, X., Zhang, Q., Liang, D., & Huang, Y. (2019). Interaction between human serum albumin and cholesterol-grafted polyglutamate as the potential carriers of protein drugs. Acta Pharmaceutica Sinica B, 9(1), 186–193. https://doi.org/10.1016/j.apsb.2018.08.001

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