Efficient targeted delivery of anticancer agents to TNBC cells remains one of the greatest challenges to developing therapies. The lack of tumor-specific markers, aggressive nature of the tumor, and unique propensity to recur and metastasize make TNBC tumors more difficult to treat than other subtypes. We propose to exploit natural ability of macrophages to target cancer cells by means of extracellular vesicles (EVs) as drug delivery vehicles for chemotherapeutic agents, paclitaxel (PTX) and doxorubicin (Dox). We demonstrated earlier that macrophage-derived EVs loaded with PTX (EV-PTX) and Dox (EV-Dox) target cancer cells and exhibited high anticancer efficacy in a mouse model of pulmonary metastases. Herein, we report a manufacture and characterization of novel EV-based drug formulations using different loading procedures that were optimized by varying pH, temperature, and sonication conditions. Selected EV-based formulations showed a high drug loading, efficient accumulation in TNBC cells in vitro, and pronounced anti-proliferation effect. Drug-loaded EVs target TNBC in vivo, including the orthotopic mouse T11 tumors in immune competent BALB/C mice, and human MDA-MB-231 tumors in athymic nu/nu mice, and abolished tumor growth. Overall, EV-based formulations can provide a novel solution to a currently unmet clinical need and reduce the morbidity and mortality of TNBC patients.

Macrophage-derived extracellular vesicles (EVs) for targeted drug delivery to TNBC tumors. Chemotherapeutics with different water solubility (Dox or PTX, i.e. hydrophilic or hydrophobic drugs, respectively) were loaded into macrophage-derived EVs through parental cells (Dox), or into naïve EVs (Dox or PTX), and their antitumor efficacy was demonstrated in mouse orthotopic TNBC model.

中文翻译：

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巨噬细胞衍生的细胞外囊泡作为三阴性乳腺癌 (TNBC) 治疗的药物递送系统。

向 TNBC 细胞有效靶向递送抗癌药物仍然是开发疗法的最大挑战之一。缺乏肿瘤特异性标志物、肿瘤的侵袭性以及独特的复发和转移倾向，使得 TNBC 肿瘤比其他亚型更难治疗。我们建议利用巨噬细胞通过细胞外囊泡 (EV) 作为化疗药物、紫杉醇 (PTX) 和阿霉素 (Dox) 的药物递送载体来靶向癌细胞的天然能力。我们早些时候证明，巨噬细胞衍生的 EVs 负载 PTX (EV-PTX) 和 Dox (EV-Dox) 靶向癌细胞，并在肺转移小鼠模型中表现出高抗癌功效。在此处，我们报告了使用通过不同 pH、温度和超声处理条件优化的不同加载程序的新型 EV 药物制剂的制造和表征。选定的基于 EV 的制剂在体外 TNBC 细胞中显示出高载药量和有效积累，并有明显的抗增殖作用。载药 EV 在体内靶向 TNBC，包括免疫活性 BALB/C 小鼠中的原位小鼠 T11 肿瘤和无胸腺 nu/nu 小鼠中的人类 MDA-MB-231 肿瘤，并消除了肿瘤生长。总体而言，基于 EV 的制剂可以为当前未满足的临床需求提供一种新的解决方案，并降低 TNBC 患者的发病率和死亡率。

巨噬细胞衍生的细胞外囊泡 (EV) 用于将药物靶向递送至 TNBC 肿瘤。将具有不同水溶性的化疗药物（Dox 或 PTX，即亲水性或疏水性药物）通过亲代细胞（Dox）加载到巨噬细胞衍生的 EVs 中，或加载到初始 EVs（Dox 或 PTX）中，并在小鼠身上证明了它们的抗肿瘤功效原位 TNBC 模型。