Focused Ultrasound Laboratory, Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115;
Department of Electrical and Computer Engineering, Tufts University, Medford, MA 02155.
Proc Natl Acad Sci U S A. 2017 Nov 28;114(48):E10281-E10290. doi: 10.1073/pnas.1713328114. Epub 2017 Nov 13.
Cavitation-facilitated microbubble-mediated focused ultrasound therapy is a promising method of drug delivery across the blood-brain barrier (BBB) for treating many neurological disorders. Unlike ultrasound thermal therapies, during which magnetic resonance thermometry can serve as a reliable treatment control modality, real-time control of modulated BBB disruption with undetectable vascular damage remains a challenge. Here a closed-loop cavitation controlling paradigm that sustains stable cavitation while suppressing inertial cavitation behavior was designed and validated using a dual-transducer system operating at the clinically relevant ultrasound frequency of 274.3 kHz. Tests in the normal brain and in the F98 glioma model in vivo demonstrated that this controller enables reliable and damage-free delivery of a predetermined amount of the chemotherapeutic drug (liposomal doxorubicin) into the brain. The maximum concentration level of delivered doxorubicin exceeded levels previously shown (using uncontrolled sonication) to induce tumor regression and improve survival in rat glioma. These results confirmed the ability of the controller to modulate the drug delivery dosage within a therapeutically effective range, while improving safety control. It can be readily implemented clinically and potentially applied to other cavitation-enhanced ultrasound therapies.
空化辅助微泡介导的聚焦超声治疗是一种有前途的方法，可以将药物递送到血脑屏障 (BBB) 中，用于治疗许多神经疾病。与超声热疗不同，在超声热疗中，磁共振测温可以作为一种可靠的治疗控制方式，而调制 BBB 破坏的实时控制而不造成血管损伤仍然是一个挑战。在这里，设计并验证了一种闭环空化控制范式，该范式在抑制惯性空化行为的同时维持稳定的空化，使用工作在临床相关超声频率 274.3 kHz 的双换能器系统。在正常大脑和 F98 神经胶质瘤模型中的体内测试表明，该控制器能够可靠地、无损伤地将预定剂量的化疗药物（脂质体阿霉素）递送到大脑中。递送到的阿霉素的最大浓度水平超过了先前（使用未控制的超声处理）显示的水平，可诱导肿瘤消退并提高大鼠神经胶质瘤的存活率。这些结果证实了该控制器能够在治疗有效范围内调节药物输送剂量，同时提高安全性控制。它可以很容易地在临床上实施，并可能应用于其他空化增强超声治疗。
