Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA 30332, USA.
School of Electrical and Computer Engineering, Georgia Institute of Technology, Atlanta, GA 30332, USA.
Adv Drug Deliv Rev. 2022 Jan;180:114043. doi: 10.1016/j.addr.2021.114043. Epub 2021 Nov 18.
Brain tumors are particularly challenging malignancies, due to their location in a structurally and functionally distinct part of the human body - the central nervous system (CNS). The CNS is separated and protected by a unique system of brain and blood vessel cells which together prevent most bloodborne therapeutics from entering the brain tumor microenvironment (TME). Recently, great strides have been made through microbubble (MB) ultrasound contrast agents in conjunction with ultrasound energy to locally increase the permeability of brain vessels and modulate the brain TME. As we elaborate in this review, this physical method can effectively deliver a wide range of anticancer agents, including chemotherapeutics, antibodies, and nanoparticle drug conjugates across a range of preclinical brain tumors, including high grade glioma (glioblastoma), diffuse intrinsic pontine gliomas, and brain metastasis. Moreover, recent evidence suggests that this technology can promote the effective delivery of novel immunotherapeutic agents, including immune check-point inhibitors and chimeric antigen receptor T cells, among others. With early clinical studies demonstrating safety, and several Phase I/II trials testing the preclinical findings underway, this technology is making firm steps towards shaping the future treatments of primary and metastatic brain cancer. By elaborating on its key components, including ultrasound systems and MB technology, along with methods for closed-loop spatial and temporal control of MB activity, we highlight how this technology can be tuned to enable new, personalized treatment strategies for primary brain malignancies and brain metastases.
脑肿瘤是一种极具挑战性的恶性肿瘤，这主要是因为其所处的位置在结构和功能上都与人体的其他部位不同，它位于中枢神经系统（CNS）中。CNS 由独特的脑和血管细胞系统分隔和保护，这一系统共同阻止了大多数血源治疗药物进入脑肿瘤微环境（TME）。最近，通过微泡（MB）超声对比剂与超声能量相结合，在局部增加血管通透性和调节脑 TME 方面取得了重大进展。正如我们在这篇综述中所阐述的那样，这种物理方法可以有效地传递广泛的抗癌药物，包括化疗药物、抗体和纳米药物偶联物，应用于一系列临床前脑肿瘤，包括高级别神经胶质瘤（胶质母细胞瘤）、弥漫性内在脑桥胶质瘤和脑转移瘤。此外，最近的证据表明，该技术可以促进新型免疫治疗药物的有效传递，包括免疫检查点抑制剂和嵌合抗原受体 T 细胞等。早期的临床研究证明了其安全性，并且正在进行几项正在测试临床前发现的 I/II 期试验，该技术正在朝着塑造原发性和转移性脑癌治疗的未来方向稳步迈进。通过详细阐述其关键组成部分，包括超声系统和 MB 技术，以及用于 MB 活性的闭环时空控制方法，我们强调了如何调整该技术以实现针对原发性脑恶性肿瘤和脑转移瘤的新的个性化治疗策略。
