Li Dan, Wang Yingli, Li Chang, Wang Qiu, Sun Bingjun, Zhang Haotian, He Zhonggui, Sun Jin
Department of Pharmaceutics, Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, China.
School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang 110016, China.
Acta Pharm Sin B. 2021 Oct;11(10):3262-3271. doi: 10.1016/j.apsb.2021.04.009. Epub 2021 Apr 18.
Tumor metastasis is responsible for chemotherapeutic failure and cancer-related death. Moreover, circulating tumor cell (CTC) clusters play a pivotal role in tumor metastasis. Herein, we develop cancer-specific calcium nanoregulators to suppress the generation and circulation of CTC clusters by cancer membrane-coated digoxin (DIG) and doxorubicin (DOX) co-encapsulated PLGA nanoparticles (CPDDs). CPDDs could precisely target the homologous primary tumor cells and CTC clusters in blood and lymphatic circulation. Intriguingly, CPDDs induce the accumulation of intracellular Ca by inhibiting Na/K-ATPase, which help restrain cell-cell junctions to disaggregate CTC clusters. Meanwhile, CPDDs suppress the epithelial-mesenchymal transition (EMT) process, resulting in inhibiting tumor cells escape from the primary site. Moreover, the combination of DOX and DIG at a mass ratio of 5:1 synergistically induces the apoptosis of tumor cells. and results demonstrate that CPDDs not only effectively inhibit the generation and circulation of CTC clusters, but also precisely target and eliminate primary tumors. Our findings present a novel approach for anti-metastasis combinational chemotherapy.
肿瘤转移是化疗失败和癌症相关死亡的原因。此外，循环肿瘤细胞（CTC）簇在肿瘤转移中起关键作用。在此，我们开发了癌症特异性钙纳米调节剂，通过癌症膜包被的地高辛（DIG）和阿霉素（DOX）共包封的聚乳酸-羟基乙酸共聚物纳米颗粒（CPDDs）来抑制CTC簇的产生和循环。CPDDs能够精确靶向血液和淋巴循环中的同源原发性肿瘤细胞和CTC簇。有趣的是，CPDDs通过抑制钠钾ATP酶诱导细胞内钙的积累，这有助于抑制细胞间连接以分解CTC簇。同时，CPDDs抑制上皮-间质转化（EMT）过程，从而抑制肿瘤细胞从原发部位逃逸。此外，DOX和DIG以5:1的质量比组合可协同诱导肿瘤细胞凋亡。结果表明，CPDDs不仅能有效抑制CTC簇的产生和循环，还能精确靶向并消除原发性肿瘤。我们的研究结果提出了一种抗转移联合化疗的新方法。
