Rudakovskaya Polina G, Barmin Roman A, Kuzmin Pavel S, Fedotkina Elena P, Sencha Alexander N, Gorin Dmitry A
Center for Photonic Science and Engineering, Skolkovo Institute of Science and Technology, Nobel Str. 3, 121205 Moscow, Russia.
Institute of Materials for Modern Energy and Nanotechnology, Dmitry Mendeleev University of Chemical Technology of Russia, Miusskaya sq. 9, 125047 Moscow, Russia.
Pharmaceutics. 2022 Jun 10;14(6):1236. 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.
超声作为一种低成本、非侵入性、无辐射的检查方法，能让治疗师更快做出决策，是临床上广泛使用的成像方式。几十年来，微泡一直被用作超声造影剂，而最近人们开始关注将其作为刺激响应型药物递送系统。开创性的微泡是Albunex，其蛋白壳由人血清白蛋白组成，于1993年进入临床应用。然而，目前的研究扩展了微泡壳蛋白的种类，使其超出了白蛋白的范围，并且蛋白微泡的应用也超出了超声成像领域。因此，本综述总结了几十年来所有已知的蛋白微泡，并对其配方和应用进行了批判性评估，以优化安全性（低毒性和高生物相容性）以及成像效率。我们全面概述了：（1）参与微泡配方的蛋白质；（2）考虑大规模生产时蛋白稳定微泡的制备特点；（3）蛋白壳微泡稳定化和功能化的关键化学因素；（4）超声成像以外的生物医学应用（多模态成像、药物/基因递送，重点关注抗癌治疗、抗菌活性、生物传感）。对当前蛋白微泡技术水平的批判性评估应使该领域聚焦于微泡配方和应用的相关策略，以便在短期内实现临床转化。因此，基于蛋白泡的平台在临床治疗诊断应用方面极具前景。
