近红外二区荧光引导下联合光热治疗靶向单羧酸转运蛋白 4 的脑胶质瘤手术。

Near-infrared II fluorescence-guided glioblastoma surgery targeting monocarboxylate transporter 4 combined with photothermal therapy.

机构信息

Department of Neurosurgery, China-Japan Union Hospital of Jilin University, Jilin University, Changchun, China; CAS Key Laboratory of Molecular Imaging, Beijing Key Laboratory of Molecular Imaging, Institute of Automation, Chinese Academy of Sciences, Beijing, China; Jilin Province Neuro-oncology Engineering Laboratory, Changchun, China; Jilin Provincial Key Laboratory of Neuro-oncology, Changchun, China.

CAS Key Laboratory of Molecular Imaging, Beijing Key Laboratory of Molecular Imaging, Institute of Automation, Chinese Academy of Sciences, Beijing, China; Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China; China National Clinical Research Center for Neurological Diseases, Beijing, China.

出版信息

EBioMedicine. 2024 Aug;106:105243. doi: 10.1016/j.ebiom.2024.105243. Epub 2024 Jul 13.

DOI:10.1016/j.ebiom.2024.105243

PMID:39004066

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11284385/

Abstract

BACKGROUND

Surgery is crucial for glioma treatment, but achieving complete tumour removal remains challenging. We evaluated the effectiveness of a probe targeting monocarboxylate transporter 4 (MCT4) in recognising gliomas, and of near-infrared window II (NIR-II) fluorescent molecular imaging and photothermal therapy as treatment strategies.

METHODS

We combined an MCT4-specific monoclonal antibody with indocyanine green to create the probe. An orthotopic mouse model and a transwell model were used to evaluate its ability to guide tumour resection using NIR-II fluorescence and to penetrate the blood-brain barrier (BBB), respectively. A subcutaneous tumour model was established to confirm photothermal therapy efficacy. Probe specificity was assessed in brain tissue from mice and humans. Finally, probe effectiveness in photothermal therapy was investigated.

FINDINGS

MCT4 was differentially expressed in tumour and normal brain tissue. The designed probe exhibited precise tumour targeting. Tumour imaging was precise, with a signal-to-background (SBR) ratio of 2.8. Residual tumour cells were absent from brain tissue postoperatively (SBR: 6.3). The probe exhibited robust penetration of the BBB. Moreover, the probe increased the tumour temperature to 50 °C within 5 min of laser excitation. Photothermal therapy significantly reduced tumour volume and extended survival time in mice without damage to vital organs.

INTERPRETATION

These findings highlight the potential efficacy of our probe for fluorescence-guided surgery and therapeutic interventions.

FUNDING

Jilin Province Department of Science and Technology (20200403079SF), Department of Finance (2021SCZ06) and Development and Reform Commission (20200601002JC); National Natural Science Foundation of China (92059207, 92359301, 62027901, 81930053, 81227901, U21A20386); and CAS Youth Interdisciplinary Team (JCTD-2021-08).

摘要

背景

手术对胶质瘤的治疗至关重要，但实现肿瘤完全切除仍然具有挑战性。我们评估了靶向单羧酸转运蛋白 4（MCT4）的探针识别胶质瘤的有效性，以及近红外二区（NIR-II）荧光分子成像和光热治疗作为治疗策略的效果。

方法

我们将 MCT4 特异性单克隆抗体与吲哚菁绿结合，制成探针。我们使用原位小鼠模型和 Transwell 模型分别评估了其使用 NIR-II 荧光引导肿瘤切除的能力和穿透血脑屏障（BBB）的能力。我们建立了皮下肿瘤模型以确认光热治疗的疗效。我们评估了探针在小鼠和人类脑组织中的特异性。最后，我们研究了探针在光热治疗中的效果。

结果

MCT4 在肿瘤和正常脑组织中表达存在差异。设计的探针表现出对肿瘤的精确靶向性。肿瘤成像精确，信号与背景（SBR）比值为 2.8。术后脑组织中无残留肿瘤细胞（SBR：6.3）。探针能有效地穿透 BBB。此外，探针在激光激发后 5 分钟内将肿瘤温度升高至 50°C。光热治疗显著减小了肿瘤体积，延长了小鼠的存活时间，且对重要器官无损伤。