The prognosis for breast cancer patients diagnosed with brain metastases is poor, with survival time measured merely in months. This can largely be attributed to the limited treatment options capable of reaching the tumor as a result of the highly restrictive blood-brain barrier (BBB). While methods of overcoming this barrier have been developed and employed with current treatment options, the majority are highly invasive and nonspecific, leading to severe neurotoxic side effects. A novel approach to address these issues is the development of therapeutics targeting receptor-mediated transport mechanisms on the BBB endothelial cell membranes. Using this approach, we intercalated doxorubicin (DOX) into a bifunctional aptamer targeting the transferrin receptor on the BBB and epithelial cell adhesion molecule (EpCAM) on metastatic cancer cells. The ability of the DOX-loaded aptamer to transcytose the BBB and selectively deliver the payload to EpCAM-positive tumors was evaluated in an in vitro model and confirmed for the first time in vivo using the MDA-MB-231 breast cancer metastasis model (MDA-MB-231Br). We show that colocalized aptamer and DOX are clearly detectable within the brain lesions 75 min postadministration. Collectively, results from this study demonstrate that through intercalation of a cytotoxic drug into the bifunctional aptamer, a therapeutic delivery vehicle can be developed for specific targeting of EpCAM-positive brain metastases.

中文翻译：

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双功能适体-多柔比星偶联物穿过血脑屏障并选择性地将其有效载荷传递给 EpCAM 阳性肿瘤细胞。

被诊断为脑转移的乳腺癌患者的预后很差，存活时间仅以月为单位。这主要是由于高度限制性的血脑屏障 (BBB) 导致能够到达肿瘤的治疗选择有限。虽然克服这一障碍的方法已被开发并用于当前的治疗方案，但大多数方法具有高度侵入性和非特异性，会导致严重的神经毒性副作用。解决这些问题的一种新方法是开发针对 BBB 内皮细胞膜上受体介导的转运机制的疗法。使用这种方法，我们将阿霉素 (DOX) 插入到双功能适体中，靶向 BBB 上的转铁蛋白受体和转移性癌细胞上的上皮细胞粘附分子 (EpCAM)。在体外模型中评估了装载 DOX 的适体转胞吞 BBB 并将有效载荷选择性递送至 EpCAM 阳性肿瘤的能力，并首次在体内使用 MDA-MB-231 乳腺癌转移模型 (MDA) 证实-MB-231Br)。我们表明，在给药后 75 分钟，共定位适体和 DOX 在脑损伤中可清楚地检测到。总的来说，这项研究的结果表明，通过将细胞毒性药物嵌入双功能适体中，可以开发一种治疗性递送载体，用于特异性靶向 EpCAM 阳性脑转移瘤。