Engineering of albumin/poly(vinylpyrrolidone-co-acrylic acid) ultrasound-responsive microbubbles by tuning the copolymer structure
Tatiana M. Estifeeva1, Anna M. Nechaeva 2, Roman A. Barmin 1, Yaroslav O. Mezhuev 2, Dmitry A. Gorin 1 and Polina G. Rudakovskaya1
1 Center for Photonic Science and Engineering, Skolkovo Institute of Science and Technology, Moscow 121205, Russia
2 Department of Biomaterials, Dmitry Mendeleev University of Chemical Technology of Russia, Moscow 125047, Russia
Abstract
Albumin-coated microbubbles are commonly used as contrast agents in ultrasound (US) imaging, but their short contrast duration limits broader clinical applications. This study explores the enhancement of bovine serum albumin (BSA)-coated microbubbles through the incorporation of N-vinyl-2-pyrrolidone and acrylic acid copolymer (P(VP–AA)) hybrids into their shells. We synthesized a library of BSA@P(VP–AA) microbubbles and identified the optimal formulation, utilizing an 8.5 kDa OM-terminated copolymer with a BSA:P(VP–AA) mass ratio of [5:1]. This formulation demonstrated a 200-fold increase in concentration, a 4-fold improvement in acoustic response, and a 2.5-fold extension in contrast duration compared to plain BSA microbubbles.
Molecular dynamics simulations revealed significant interactions between BSA and copolymers, especially with neutral and positively charged amino acids, leading to stable microbubble shells. ATR-FTIR spectroscopy confirmed the presence of stable protein-copolymer complexes, indicating that the introduction of copolymers does not compromise the structural integrity of BSA but enhances stability and performance.
In vivo cardiac ultrasound imaging in rats demonstrated that BSA@P(VP–AA) OM microbubbles provided significantly brighter and longer-lasting contrast than plain BSA microbubbles, maintaining a strong signal up to 5 minutes post-injection. This superior performance suggests potential for multimodal applications, such as combining US imaging with optoacoustic techniques or enhancing photodynamic cancer therapy. Additionally, biocompatibility and biodistribution studies confirmed the safety of these microbubbles, with no observed acute toxicity or adverse effects. These findings highlight the potential of tailored protein-copolymer hybrids for advanced multimodal imaging and therapeutic applications in biomedical optics and photonics.
Speaker
Tatiana M. Estifeeva
Center for Photonic Science and Engineering, Skolkovo Institute of Science and Technology, Moscow, Russia
Russia
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