MR-guided focused ultrasound increases antibody delivery to nonenhancing high-grade glioma
MR-guided focused ultrasound increases antibody delivery to nonenhancing high-grade glioma
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DOI：
10.1093/noajnl/vdaa030
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发表时间：
2020-01-01
期刊：
影响因子：
--
通讯作者：
Puttick, Simon
中科院分区：
文献类型：
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作者：
Brighi, Caterina;Reid, Lee;Puttick, Simon
背景。高级别胶质瘤（HGG）仍然是一个顽固性的临床问题，尽管几十年的研究。改善预后的一个主要挑战是目前的治疗策略无法解决浸润性肿瘤细胞扩展到原发肿瘤肿块边缘以外的临床显著负担。这些细胞不能通过手术切除，也不能通过放射治疗有效靶向。这种肿瘤细胞群的治疗靶向受到完整血脑屏障（BBB）存在的显著阻碍。在这项研究中，我们对核磁共振引导的聚焦超声（FUS）的有效性进行了临床前研究，以暂时破坏血脑屏障，从而允许选择性地将肿瘤靶向抗体递送到浸润性肿瘤。方法。结构MRI、动态对比增强MRI和组织学被用来充分表征患者来源的异种移植（PDX）原位小鼠HGG模型的磁共振增强特性，并建立一个可重复的、健壮的非增强HGG模型。然后使用PET-CT成像技术评估FUS在非增强HGG区域和邻近非靶向肿瘤组织中增加zr -89放射标记抗体浓度的功效。结果。HGG的PDX小鼠模型在完整血脑屏障后面有明显的肿瘤负荷。非增强肿瘤区域抗体摄取的增加与fus靶向体积成正比。在血脑屏障完整的肿瘤中，FUS局部增加了FUS靶向区域的抗体摄取，而非靶向区域不受影响。结论。FUS暴露成功地使血脑屏障暂时中断，定位于特异性靶向，非增强，浸润性肿瘤区域，并且全身给药抗体的递送显着增加。
Background. High-grade glioma (HGG) remains a recalcitrant clinical problem despite many decades of research. A major challenge in improving prognosis is the inability of current therapeutic strategies to address a clinically significant burden of infiltrating tumor cells that extend beyond the margins of the primary tumor mass. Such cells cannot be surgically excised nor efficiently targeted by radiation therapy. Therapeutic targeting of this tumor cell population is significantly hampered by the presence of an intact blood-brain barrier (BBB). In this study, we performed a preclinical investigation of the efficiency of MR-guided Focused Ultrasound (FUS) to temporarily disrupt the BBB to allow selective delivery of a tumor-targeting antibody to infiltrating tumor. Methods. Structural MRI, dynamic-contrast enhancement MRI, and histology were used to fully characterize the MR-enhancing properties of a patient-derived xenograft (PDX) orthotopic mouse model of HGG and to develop a reproducible, robust model of nonenhancing HGG. PET-CT imaging techniques were then used to evaluate the efficacy of FUS to increase Zr-89-radiolabeled antibody concentration in nonenhancing HGG regions and adjacent non-targeted tumor tissue. Results. The PDX mouse model of HGG has a significant tumor burden lying behind an intact BBB. Increased antibody uptake in nonenhancing tumor regions is directly proportional to the FUS-targeted volume. FUS locally increased antibody uptake in FUS-targeted regions of the tumor with an intact BBB, while leaving untargeted regions unaffected. Conclusions. FUS exposure successfully allowed temporary BBB disruption, localized to specifically targeted, nonenhancing, infiltrating tumor regions and delivery of a systemically administered antibody was significantly increased.