Molotkov Andrei, Carberry Patrick, Dolan Martin A, Joseph Simon, Idumonyi Sidney, Oya Shunichi, Castrillon John, Konofagou Elisa E, Doubrovin Mikhail, Lesser Glenn J, Zanderigo Francesca, Mintz Akiva
Department of Radiology, Columbia University Medical Center, 722 West 168th Street, New York, NY 10032, USA.
Department of Biomedical Engineering, Columbia University Medical Center, 722 West 168th Street, New York, NY 10032, USA.
Pharmaceutics. 2021 Mar 18;13(3):405. doi: 10.3390/pharmaceutics13030405.
Glioblastoma (GBM) is the most common primary adult brain malignancy with an extremely poor prognosis and a median survival of fewer than two years. A key reason for this high mortality is that the blood-brain barrier (BBB) significantly restricts systemically delivered therapeutics to brain tumors. High-intensity focused ultrasound (HIFU) with microbubbles is a methodology being used in clinical trials to noninvasively permeabilize the BBB for systemic therapeutic delivery to GBM. Topotecan is a topoisomerase inhibitor used as a chemotherapeutic agent to treat ovarian and small cell lung cancer. Studies have suggested that topotecan can cross the BBB and can be used to treat brain metastases. However, pharmacokinetic data demonstrated that topotecan peak concentration in the brain extracellular fluid after systemic injection was ten times lower than in the blood, suggesting less than optimal BBB penetration by topotecan. We hypothesize that HIFU with microbubbles treatment can open the BBB and significantly increase topotecan concentration in the brain. We radiolabeled topotecan with C and acquired static and dynamic positron emission tomography (PET) scans to quantify [C] topotecan uptake in the brains of normal mice and mice after HIFU treatment. We found that HIFU treatments significantly increased [C] topotecan brain uptake. Moreover, kinetic analysis of the [C] topotecan dynamic PET data demonstrated a substantial increase in [C] topotecan volume of distribution in the brain. Furthermore, we found a decrease in [C] topotecan brain clearance, confirming the potential of HIFU to aid in the delivery of topotecan through the BBB. This opens the potential clinical application of [C] topotecan as a tool to predict topotecan loco-regional brain concentration in patients with GBMs undergoing experimental HIFU treatments.
胶质母细胞瘤（GBM）是最常见的原发性成人大脑恶性肿瘤，预后极差，中位生存期不到两年。造成这种高死亡率的一个关键原因是血脑屏障（BBB）显著限制了全身给药的治疗药物进入脑肿瘤。带有微泡的高强度聚焦超声（HIFU）是一种正在临床试验中使用的方法，用于无创地使血脑屏障通透，以便将全身治疗药物递送至GBM。拓扑替康是一种拓扑异构酶抑制剂，用作治疗卵巢癌和小细胞肺癌的化疗药物。研究表明，拓扑替康可以穿过血脑屏障，可用于治疗脑转移瘤。然而，药代动力学数据表明，全身注射后拓扑替康在脑细胞外液中的峰值浓度比在血液中低十倍，这表明拓扑替康对血脑屏障的穿透效果欠佳。我们假设，带有微泡的HIFU治疗可以打开血脑屏障，并显著提高拓扑替康在脑中的浓度。我们用碳-11标记拓扑替康，并进行静态和动态正电子发射断层扫描（PET），以量化正常小鼠和接受HIFU治疗后的小鼠脑中[碳-11]拓扑替康的摄取情况。我们发现，HIFU治疗显著增加了[碳-11]拓扑替康在脑中的摄取。此外，对[碳-11]拓扑替康动态PET数据的动力学分析表明，[碳-11]拓扑替康在脑中的分布容积大幅增加。此外，我们发现[碳-11]拓扑替康在脑中的清除率降低，证实了HIFU有助于拓扑替康通过血脑屏障递送的潜力。这开启了[碳-11]拓扑替康作为一种工具的潜在临床应用，用于预测接受实验性HIFU治疗的GBM患者中拓扑替康的局部脑浓度。
