Breast cancer brain metastases (BCBMs) represent a major cause of morbidity and mortality among patients with breast cancer. Chemotherapy, which is widely used to treat tumors outside of the brain, is often ineffective on BCBMs due to its inability to efficiently cross the blood-brain barrier (BBB). Although the BBB is partially disrupted in tumor lesions, it remains intact enough to prevent most therapeutics from entering the brain. Here, we report a nanotechnology approach that can overcome the BBB through synthesis of lexiscan-loaded, AMD3100-conjugated, shrinkable NPs, or LANPs. LANPs respond to neutrophil elastase-enriched tumor microenvironment by shrinking in size and disrupt the BBB in tumors through lexiscan-mediated modulation. LANPs recognize tumor cells through the interaction between AMD3100 and CXCR4, which are expressed in metastatic tumor cells. We demonstrate that the integration of tumor responsiveness, tumor targeting, and BBB penetration enables LANPs to penetrate metastatic lesions in the brain with high efficiency, and, when doxorubicin was encapsulated, LANPs effectively inhibited tumor growth and prolonged the survival of tumor-bearing mice. Due to their high efficiency in penetrating the BBB for BCBMs treatment, LANPs have the potential to be translated into clinical applications for improved treatment of patients with BCBMs.

中文翻译：

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自催化递送脑肿瘤靶向、尺寸可收缩的纳米颗粒用于治疗乳腺癌脑转移。

乳腺癌脑转移（BCBM）是乳腺癌患者发病和死亡的主要原因。化疗广泛用于治疗脑外肿瘤，但由于无法有效穿过血脑屏障 (BBB)，因此通常对 BCBM 无效。尽管血脑屏障在肿瘤病变中被部分破坏，但它仍然保持完整，足以阻止大多数治疗药物进入大脑。在这里，我们报告了一种纳米技术方法，该方法可以通过合成加载词典的、AMD3100 共轭的、可收缩的 NP 或 LANP 来克服 BBB。LANP 通过缩小尺寸来响应富含中性粒细胞弹性蛋白酶的肿瘤微环境，并通过 lexiscan 介导的调节破坏肿瘤中的 BBB。LANP通过AMD3100和CXCR4之间的相互作用来识别肿瘤细胞，CXCR4在转移性肿瘤细胞中表达。我们证明，肿瘤反应性、肿瘤靶向性和血脑屏障渗透性的整合使 LANP 能够高效地渗透大脑中的转移灶，并且当封装阿霉素时，LANP 有效抑制肿瘤生长并延长荷瘤小鼠的生存期。由于 LANP 在穿透 BBB 进行 BCBM 治疗方面效率很高，因此有可能转化为临床应用，以改善 BCBM 患者的治疗。