Zhou Mengyuan, Lin Yuanyuan, Chen Haiyan, Zhao Mei, Zeng Yuteng, Hu Xiaoxiao, Tang Puxian, Fu Yuxuan, Wei Lin, Han Liang
Jiangsu Key Laboratory of Neuropsychiatric Diseases Research, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China; Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou 215123, China.
Jiangsu Key Laboratory of Neuropsychiatric Diseases Research, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China.
J Control Release. 2024 Nov;375:116-126. doi: 10.1016/j.jconrel.2024.09.003. Epub 2024 Sep 6.
Many chemotherapeutic and molecular targeted drugs have been used to treat brain metastases, e.g., anti-angiogenic vandetanib. However, the blood-brain barrier and brain-specific resistance mechanisms make these systemic therapeutic approaches inefficacious. Brain metastatic cancer cells could mimic neurons to upregulate multiple serpins and secrete them into the extracellular environment to reduce local plasmin production to promote L1CAM-mediated vessel co-option and resist anti-angiogenesis therapy. Here, we developed brain-tumor-seeking and serpin-inhibiting outer membrane vesicles (DE@OMVs) to traverse across the blood-brain barrier, bypass neurons, and specially enter metastatic cancer cells via targeting GRP94 and vimentin. Through specific delivery of dexamethasone and embelin, reduced serpin secretion, restored plasmin production, significant L1CAM inactivation and tumor cell apoptosis were specially found in intracranial metastatic regions, leading to delayed tumor growth and prolonged survival in mice with brain metastases. By combining the brain-tumor-seeking properties with the regulation of the serpin/plasminogen activator/plasmin/L1CAM axis, this study provides a potent and highly-selective systemic therapeutic option for brain metastases.
许多化疗药物和分子靶向药物已被用于治疗脑转移瘤，例如抗血管生成药物凡德他尼。然而，血脑屏障和脑特异性耐药机制使得这些全身治疗方法无效。脑转移癌细胞可以模仿神经元上调多种丝氨酸蛋白酶抑制剂，并将它们分泌到细胞外环境中，以减少局部纤溶酶的产生，从而促进L1细胞黏附分子（L1CAM）介导的血管共选择，并抵抗抗血管生成治疗。在此，我们开发了靶向脑肿瘤并抑制丝氨酸蛋白酶抑制剂的外膜囊泡（DE@OMVs），使其能够穿越血脑屏障，绕过神经元，并通过靶向葡萄糖调节蛋白94（GRP94）和波形蛋白特异性进入转移癌细胞。通过特异性递送地塞米松和 embelin，在颅内转移区域特别发现丝氨酸蛋白酶抑制剂分泌减少、纤溶酶产生恢复、L1CAM显著失活和肿瘤细胞凋亡，从而导致脑转移小鼠的肿瘤生长延迟和生存期延长。通过将靶向脑肿瘤的特性与对丝氨酸蛋白酶抑制剂/纤溶酶原激活剂/纤溶酶/L1CAM轴的调节相结合，本研究为脑转移瘤提供了一种有效且高度选择性的全身治疗选择。
