Transferrin Receptor-Targeted Nonspherical Microbubbles for Blood-Brain Barrier Sonopermeation.
Transferrin Receptor-Targeted Nonspherical Microbubbles for Blood-Brain Barrier Sonopermeation.
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用于血脑屏障超声渗透的转铁蛋白受体靶向非球形微泡。
DOI：
10.1002/adma.202308150
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Kiessling,Fa
中科院分区：
文献类型：
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作者：
Dasgupta,Anshuman;Sun,Tao;Rama,Elena;Motta,Alessandro;Zhang,Yongzhi;Power,Chanikarn;Moeckel,Diana;Fletcher,Stecia-Marie;Moosavifar,Mirjavad;Barmin,Roman;Porte,Céline;Buhl,EvaMiriam;Bastard,Céline;Pallares,RogerM;Kiessling,Fa
微泡（MB）被广泛用于超声（US）成像和药物递送。由于表面张力，MB通常为球形。当加热至高于其玻璃化转变温度时，聚合物基MB可被机械拉伸以获得各向异性形状，从而赋予其US介导的血脑屏障（BBB）渗透的独特功能。这里显示，非球形MB可以用BBB特异性靶向配体进行表面修饰，从而促进与脑中血管的结合和超声渗透。通过球形聚（氰基丙烯酸丁酯）MB的1D拉伸和随后用抗转铁蛋白受体（TfR）抗体对其外壳进行功能化，产生主动靶向的棒状MB。使用US和光学成像，证明了在体外和体内，非球形抗TfR-MB比球形抗TfR-MB更有效地结合BBB内皮。与球形BBB靶向MB相比，BBB相关各向异性MB产生更强的空化信号，并显著增强BBB渗透和模型药物的递送。这些发现证实了抗体修饰的非球形MB用于靶向和触发药物递送至大脑的潜力。
Microbubbles (MB) are widely used for ultrasound (US) imaging and drug delivery. MB are typically spherically shaped, due to surface tension. When heated above their glass transition temperature, polymer‐based MB can be mechanically stretched to obtain an anisotropic shape, endowing them with unique features for US‐mediated blood–brain barrier (BBB) permeation. It is here shown that nonspherical MB can be surface‐modified with BBB‐specific targeting ligands, thereby promoting binding to and sonopermeation of blood vessels in the brain. Actively targeted rod‐shaped MB are generated via 1D stretching of spherical poly(butyl cyanoacrylate) MB and via subsequently functionalizing their shell with antitransferrin receptor (TfR) antibodies. Using US and optical imaging, it is demonstrated that nonspherical anti‐TfR‐MB bind more efficiently to BBB endothelium than spherical anti‐TfR‐MB, both in vitro and in vivo. BBB‐associated anisotropic MB produce stronger cavitation signals and markedly enhance BBB permeation and delivery of a model drug as compared to spherical BBB‐targeted MB. These findings exemplify the potential of antibody‐modified nonspherical MB for targeted and triggered drug delivery to the brain.