Microbubbles Stabilized by Protein Shell: From Pioneering Ultrasound Contrast Agents to Advanced Theranostic Systems

• Published in: Pharmaceutics Vol. 14; no. 6; p. 1236
• Main Authors: Rudakovskaya, Polina G, Barmin, Roman A, Kuzmin, Pavel S, Fedotkina, Elena P, Sencha, Alexander N, Gorin, Dmitry A
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 10.06.2022; MDPI
• Subjects: albumin; Binding sites; Chemical bonds; Contrast agents; Drug delivery systems; FDA approval; Hemoglobin; Lipids; lysozyme; microbubbles; Molecular weight; Perfluorocarbons; Proteins; Regulatory approval; Review; Surfactants; Ultrasonic imaging; ultrasound; United States > US; Norway; lysozyme; microbubbles; oleosin; contrast agents; proteins; albumin; theranostics; drug delivery; ultrasound
• ISSN: 1999-4923; 1999-4923
• DOI: 10.3390/pharmaceutics14061236

Ultrasound is a widely-used imaging modality in clinics as a low-cost, non-invasive, non-radiative procedure allowing therapists faster decision-making. Microbubbles have been used as ultrasound contrast agents for decades, while recent attention has been attracted to consider them as stimuli-responsive drug delivery systems. Pioneering microbubbles were Albunex with a protein shell composed of human serum albumin, which entered clinical practice in 1993. However, current research expanded the set of proteins for a microbubble shell beyond albumin and applications of protein microbubbles beyond ultrasound imaging. Hence, this review summarizes all-known protein microbubbles over decades with a critical evaluation of formulations and applications to optimize the safety (low toxicity and high biocompatibility) as well as imaging efficiency. We provide a comprehensive overview of (1) proteins involved in microbubble formulation, (2) peculiarities of preparation of protein stabilized microbubbles with consideration of large-scale production, (3) key chemical factors of stabilization and functionalization of protein-shelled microbubbles, and (4) biomedical applications beyond ultrasound imaging (multimodal imaging, drug/gene delivery with attention to anticancer treatment, antibacterial activity, biosensing). Presented critical evaluation of the current state-of-the-art for protein microbubbles should focus the field on relevant strategies in microbubble formulation and application for short-term clinical translation. Thus, a protein bubble-based platform is very perspective for theranostic application in clinics.