Institute of Oceanography, Minjiang University, Fuzhou, Fujian 350108, China; Cancer Metastasis Alert and Prevention Center, College of Chemistry; Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention and Chemotherapy, Fuzhou University, Fuzhou, Fujian 350116, China.
Cancer Metastasis Alert and Prevention Center, College of Chemistry; Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention and Chemotherapy, Fuzhou University, Fuzhou, Fujian 350116, China.
J Control Release. 2021 Mar 10;331:404-415. doi: 10.1016/j.jconrel.2021.01.030. Epub 2021 Jan 22.
Each type of cancer has its own specific metastatic route developed by disseminating circulating tumor cells (CTCs) and related extracellular vesicles to the target organ, i.e., metastasis organotropism. Tumor-derived small extracellular vesicles (herein exosomes, EXO) play an important role in determining cancer organotropic metastases to pre-metastasis niches. We therefore hypothesized that drug-loaded EXO may mix well with their companion small extracellular vesicles to specifically target the aimed metastatic organ via organotropism. Here, we demonstrate that the circulating breast-cancer-derived EXO loaded with doxorubicin (EXO-DOX) can mingled with their original companion EXO and inhibit breast cancer metastasis to lungs. The CD47 on the EXO-DOX prevented EXO-DOX from immune attack and prolonged their circulation in blood. The tissue distribution ratio of EXO-DOX is identical to the ratio of their companion EXO due to the specific affinity of EXO to integrins in targeted tissues. Quantitative accumulation of EXO-DOX in the mouse lungs is proportional to the organotropism of the circulating breast cancer cells that disseminate from subcutaneously-implanted human breast cancer cells in mice. EXO-DOX inhibited angiogenesis and cancer cell proliferation, resulting in prevention of breast cancer metastasis to the lungs. This study opens a novel path to use Trojan small extracellular vesicles for specifically controlled release of active components by small extracellular vesicles organotropism mechanism to the targeted organ for disease chemoprevention.
每种癌症都有其特定的转移途径，通过循环肿瘤细胞 (CTCs) 和相关的细胞外囊泡扩散到靶器官，即转移器官嗜性。肿瘤来源的小细胞外囊泡（本文中称为外泌体，EXO）在决定癌症向转移性前位器官的器官嗜性转移中起着重要作用。因此，我们假设载药 EXO 可能与它们的原始伴侣 EXO 很好地混合，通过器官嗜性特异性靶向目标转移性器官。在这里，我们证明了载有多柔比星的循环乳腺癌衍生 EXO（EXO-DOX）可以与它们的原始伴侣 EXO 混合，并抑制乳腺癌向肺部转移。EXO-DOX 上的 CD47 可防止 EXO-DOX 受到免疫攻击，并延长其在血液中的循环时间。由于 EXO 与靶向组织中的整合素具有特异性亲和力，因此 EXO-DOX 的组织分布比例与它们的伴侣 EXO 的比例相同。EXO-DOX 在小鼠肺部的定量积累与从皮下植入的人类乳腺癌细胞在小鼠中扩散的循环乳腺癌细胞的器官嗜性成正比。EXO-DOX 抑制血管生成和癌细胞增殖，从而防止乳腺癌向肺部转移。这项研究为利用特洛伊小细胞外囊泡通过小细胞外囊泡器官嗜性机制特异性控制活性成分的释放开辟了一条新途径，将活性成分靶向器官用于疾病化学预防。
