Department of Surgery , Washington University School of Medicine , St. Louis , Missouri 63110 , United States.
ACS Nano. 2019 Feb 26;13(2):1078-1096. doi: 10.1021/acsnano.8b08872. Epub 2019 Jan 4.
It is extremely difficult for cancer chemotherapy to control the peritoneal metastasis of advanced ovarian carcinoma given its inability to target disseminated tumors and the severe toxic side effects on healthy organs. Here, we report antitumor M1 macrophages developed as live-cell carriers that deliver anticancer drugs for the treatment of the metastatic ovarian carcinoma. Engineered doxorubicin-loaded M1 macrophages (M1-Dox) significantly enhanced tumor tropism by upregulation of CCR2 and CCR4 compared with their parent cells. Meanwhile, M1-Dox inhibited doxorubicin-induced tumor invasion, whereas commercial Lipo-Dox did not limit these side effects. Importantly, our data uncovered a drug delivery mechanism by which M1-Dox transferred drug cargoes into tumor cells via a tunneling nanotube pathway. The tunneling nanotube network acted as a transportation expressway for ultrafast drug delivery of M1-Dox, leading to efficient ovarian carcinoma cell death. Furthermore, genetic, pharmacological, and physical perturbations of these tunneling nanotubes obviously decreased drug transfer of M1-Dox, which further validated the evident correlation between drug delivery of M1-Dox and tunneling nanotubes. Finally, in peritoneal metastatic ovarian carcinoma-burdened mice, M1-Dox specifically penetrated into and accumulated deep within disseminated neoplastic lesions compared with commercial Lipo-Dox, resulting in reducing metastatic tumors to a nearly undetectable level and significantly increasing overall survival. Overall, the strategy of engineered macrophages for ultrafast and accurate drug delivery via the tunneling nanotubular expressway potentially revolutionizes the treatment of metastatic ovarian carcinoma.
由于癌症化疗无法针对播散性肿瘤，且对健康器官有严重的毒副作用，因此很难控制晚期卵巢癌的腹膜转移。在这里，我们报告了作为活细胞载体开发的抗肿瘤 M1 巨噬细胞，用于输送抗癌药物治疗转移性卵巢癌。与亲本细胞相比，载有阿霉素的工程化 M1 巨噬细胞（M1-Dox）通过上调 CCR2 和 CCR4 显著增强了肿瘤趋向性。同时，M1-Dox 抑制了阿霉素诱导的肿瘤侵袭，而商业 Lipo-Dox 则不能限制这些副作用。重要的是，我们的数据揭示了一种药物递送机制，通过该机制，M1-Dox 通过隧道纳米管途径将药物货物转移到肿瘤细胞中。隧道纳米管网络充当了 M1-Dox 的超快药物递送的运输高速公路，导致卵巢癌细胞的有效死亡。此外，这些隧道纳米管的遗传、药理学和物理扰动明显降低了 M1-Dox 的药物转移，这进一步验证了 M1-Dox 的药物递送与隧道纳米管之间的明显相关性。最后，在患有腹膜转移性卵巢癌的小鼠中，与商业 Lipo-Dox 相比，M1-Dox 特异性地穿透并在弥漫性肿瘤病变深处积累，从而将转移性肿瘤减少到几乎无法检测的水平，并显著提高了总生存率。总之，通过隧道纳米管高速公路工程化巨噬细胞用于超快和准确药物递送的策略可能彻底改变转移性卵巢癌的治疗方法。
