Wang Lulu, Zhao Alan H, Arledge Chad A, Xing Fei, Chan Michael D, Brekken Rolf A, Habib Amyn A, Zhao Dawen
Department of Biomedical Engineering, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
School of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA.
Cancers (Basel). 2024 Sep 5;16(17):3088. doi: 10.3390/cancers16173088.
Brain metastasis is the most common intracranial malignancy in adults. The prognosis is extremely poor, partly because most patients have more than one brain lesion, and the currently available therapies are nonspecific or inaccessible to those occult metastases due to an impermeable blood-tumor barrier (BTB). Phosphatidylserine (PS) is externalized on the surface of viable endothelial cells (ECs) in tumor blood vessels. In this study, we have applied a PS-targeting antibody to assess brain metastases in mouse models. Fluorescence microscopic imaging revealed that extensive PS exposure was found exclusively on vascular ECs of brain metastases. The highly sensitive and specific binding of the PS antibody enables individual metastases, even micrometastases containing an intact BTB, to be clearly delineated. Furthermore, the conjugation of the PS antibody with a fluorescence dye, IRDye 800CW, or a radioisotope, I, allowed the clear visualization of individual brain metastases by optical imaging and autoradiography, respectively. In conclusion, we demonstrated a novel strategy for targeting brain metastases based on our finding that abundant PS exposure occurs on blood vessels of brain metastases but not on normal brain, which may be useful for the development of imaging and targeted therapeutics for brain metastases.
脑转移是成人中最常见的颅内恶性肿瘤。其预后极差，部分原因是大多数患者有不止一个脑病灶，且由于不可渗透的血瘤屏障（BTB），目前可用的治疗方法是非特异性的，或者对那些隐匿性转移灶无效。磷脂酰丝氨酸（PS）在肿瘤血管中存活的内皮细胞（ECs）表面外化。在本研究中，我们应用了一种靶向PS的抗体来评估小鼠模型中的脑转移。荧光显微镜成像显示，广泛的PS暴露仅在脑转移灶的血管内皮细胞上发现。PS抗体的高灵敏度和特异性结合使得单个转移灶，甚至是含有完整血瘤屏障的微转移灶都能被清晰勾勒出来。此外，PS抗体与荧光染料IRDye 800CW或放射性同位素I的结合，分别通过光学成像和放射自显影实现了单个脑转移灶的清晰可视化。总之，基于我们的发现，即脑转移灶血管上存在大量PS暴露而正常脑则没有，我们证明了一种靶向脑转移的新策略，这可能有助于开发脑转移的成像和靶向治疗方法。
