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Abstract：
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 Ca2+ 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. In vitro and in vivo 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.
摘要：
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。在这里，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）和多柔比星（DOX）共包裹的PLGA纳米颗粒（CPDD）来抑制CTC簇的产生和循环。CPDD可以精确靶向血液和淋巴循环中的同源原代肿瘤细胞和CTC簇。有趣的是，CPDDs通过抑制Na+/K+-ATP酶诱导细胞内Ca2+的积累,这有助于抑制细胞-细胞连接解聚CTC簇。同时,CPDD抑制上皮-间质转化（EMT）过程，导致抑制肿瘤细胞从原发部位逃逸。此外，DOX和DIG以5:1的质量比的组合协同诱导肿瘤细胞的凋亡。体内外实验结果表明,CPDDs不仅能有效抑制CTC簇的产生和循环,而且精确靶向和消除原发性肿瘤。我们的发现为抗转移联合化疗提供了一种新的方法。
