Minhang Hospital and Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy , Fudan University , Shanghai 201203 , China.
State Key Laboratory of Medical Neurobiology, School of Basic Medical Sciences and Institutes of Brain Science , Fudan University , Shanghai 200032 , China.
ACS Appl Mater Interfaces. 2019 May 1;11(17):15241-15250. doi: 10.1021/acsami.9b00227. Epub 2019 Apr 17.
Glioma is the most frequent form of malignant brain tumors. Surgical debulking is a major strategy for glioma treatment. However, there is a great challenge for the neurosurgeons to intraoperatively identify the true margins of glioma because of its infiltrative nature. Tumor residues or microscopic satellite foci left in the resection bed are the main reasons leading to early recurrence as well as poor prognosis. In this study, a surface-enhanced resonance Raman scattering (SERRS) probe was developed to intraoperatively guide glioma resection. In this probe, molecular reporters with absorptive maxima at the near-infrared wavelength range were covalently functionalized on the surface of gold nanostars. This SERRS probe demonstrated an ultrahigh sensitivity with a detection limit of 5.0 pM in aqueous solution. By the development of glioma xenografts in a mouse dorsal skin window chamber, extravasation of this probe from leaky tumor vasculature as functions of time and distance to tumor boundary was investigated. Importantly, the invasive margin of the tumor xenograft was demarcated by this probe with a high signal-to-background ratio. Preoperative magnetic resonance imaging (MRI) first defined the position of orthotopic glioma xenografts in the brain of rat models, and the craniotomy plan was designed. The brain tumor was then excised intraoperatively step-by-step with the assistance of a handheld Raman scanner till the Raman signals of the probe completely disappeared in the resection bed. Notably, longitudinal MRI showed that SERRS-guided surgery significantly reduced the tumor recurrence rate and improved the overall survival of rat models compared with the white light-guided surgery. Overall, this work demonstrates the prognostic benefit of SERRS-guided glioma surgery in animal models. Because delineation of tumor-invasive margins is a common challenge faced by the surgeons, this SERRS probe with a picomolar detection limit holds the promise in improving the surgical outcome of different types of infiltrated tumors.
神经胶质瘤是最常见的恶性脑肿瘤。手术切除是治疗神经胶质瘤的主要策略。然而，由于其浸润性，神经外科医生在术中识别神经胶质瘤的真正边界具有很大的挑战性。肿瘤残留或切除床中留下的微观卫星灶是导致早期复发和预后不良的主要原因。在这项研究中，开发了一种表面增强共振拉曼散射（SERRS）探针，用于术中指导神经胶质瘤切除。在该探针中，将吸收峰在近红外波长范围内的分子报告分子通过共价键功能化在金纳米星的表面上。该 SERRS 探针在水溶液中具有超灵敏性，检测限为 5.0 pM。通过在小鼠背部皮肤窗室中建立神经胶质瘤异种移植模型，研究了该探针从渗漏的肿瘤血管中外渗的时间和距离依赖性。重要的是，该探针以高信号与背景比标记了肿瘤异种移植的侵袭性边界。术前磁共振成像（MRI）首先定义了大鼠模型中原位神经胶质瘤异种移植的位置，并设计了开颅计划。然后，在手持 Raman 扫描仪的协助下，将脑肿瘤一步一步地切除，直到探针的 Raman 信号在切除床上完全消失。值得注意的是，纵向 MRI 显示，与白光引导手术相比，SERRS 引导手术显著降低了肿瘤复发率，并提高了大鼠模型的总生存率。总体而言，这项工作证明了 SERRS 引导神经胶质瘤手术在动物模型中的预后益处。由于肿瘤侵袭性边界的描绘是外科医生面临的共同挑战，因此这种具有皮摩尔检测限的 SERRS 探针有望改善不同类型浸润性肿瘤的手术结果。
