Molecular Imaging Innovations Institute, Department of Radiology, Weill Cornell Medicine, New York, New York.
Laboratory of Comparative Pathology, Center of Comparative Medicine and Pathology, Memorial Sloan Kettering Cancer Center, The Rockefeller University, Weill Cornell Medicine, New York, New York.
Neuro Oncol. 2020 Oct 14;22(10):1495-1504. doi: 10.1093/neuonc/noaa101.
Diffuse intrinsic pontine glioma (DIPG) is a highly lethal malignancy that occurs predominantly in children. DIPG is inoperable and post-diagnosis survival is less than 1 year, as conventional chemotherapy is ineffective. The intact blood-brain barrier (BBB) blocks drugs from entering the brain. Convection-enhanced delivery (CED) is a direct infusion technique delivering drugs to the brain, but it suffers from rapid drug clearance. Our goal is to overcome the delivery barrier via CED and maintain a therapeutic concentration at the glioma site with a payload-adjustable peptide nanofiber precursor (NFP) that displays a prolonged retention property as a drug carrier.
The post-CED retention of 89Zr-NFP was determined in real time using PET/CT imaging. Emtansine (DM1), a microtubule inhibitor, was conjugated to NFP. The cytotoxicity of the resulting DM1-NFP was tested against patient-derived DIPG cell lines. The therapeutic efficacy was evaluated in animals bearing orthotopic DIPG, according to glioma growth (measured using bioluminescence imaging) and the long-term survival.
DM1-NFP demonstrated potency against multiple glioma cell lines. The half-maximal inhibitory concentration values were in the nanomolar range. NFP remained at the infusion site (pons) for weeks, with a clearance half-life of 60 days. DM1-NFP inhibited glioma progression in animals, and offered a survival benefit (median survival of 62 days) compared with the untreated controls (28 days) and DM1-treated animal group (26 days).
CED, in combination with DM1-NFP, complementarily functions to bypass the BBB, prolong drug retention at the fusion site, and maintain an effective therapeutic effect against DIPG to improve treatment outcome.
弥漫性内在脑桥神经胶质瘤（DIPG）是一种主要发生在儿童身上的高度致命性恶性肿瘤。由于常规化疗无效，DIPG 无法手术，诊断后存活时间不到 1 年。完整的血脑屏障（BBB）阻止药物进入大脑。对流增强递送（CED）是一种将药物直接递送到大脑的输注技术，但它存在药物清除过快的问题。我们的目标是通过 CED 克服递送障碍，并使用可调节有效载荷的肽纳米纤维前体（NFP）来维持治疗浓度，该前体作为药物载体具有延长保留特性。
使用 PET/CT 成像实时确定 CED 后 NFP 的保留情况。将微管抑制剂恩坦辛（DM1）连接到 NFP 上。测试所得 DM1-NFP 对源自患者的 DIPG 细胞系的细胞毒性。根据神经胶质瘤的生长（通过生物发光成像测量）和长期存活情况，在患有原位 DIPG 的动物中评估治疗效果。
DM1-NFP 对多种神经胶质瘤细胞系具有效力。半数最大抑制浓度值在纳摩尔范围内。NFP 在数周内仍保留在输注部位（脑桥），清除半衰期为 60 天。DM1-NFP 抑制了动物的神经胶质瘤进展，并与未治疗对照（28 天）和 DM1 治疗的动物组（26 天）相比，提供了生存获益（中位存活期为 62 天）。
CED 与 DM1-NFP 联合使用，互补地绕过 BBB，延长药物在融合部位的保留时间，并维持针对 DIPG 的有效治疗效果，以改善治疗结果。
