Biomimetic carrier-free nanoparticle delivers digoxin and doxorubicin to exhibit synergetic antitumor activity in vitro and in vivo
Biomimetic carrier-free nanoparticle delivers digoxin and doxorubicin to exhibit synergetic antitumor activity in vitro and in vivo
复制标题
仿生无载体纳米颗粒递送地高辛和阿霉素，在体外和体内表现出协同抗肿瘤活性
DOI：
10.1016/j.cej.2020.126801
复制
发表时间：
2021-02
影响因子：
15.1
通讯作者：
Kong Dexin
中科院分区：
文献类型：
--
作者：
Zhang Zhe;Wang Yingying;Ma Qian;Zhang Shaolu;Liu Hongyan;Zhao Baoquan;Liu Rui;Wang Wei;Du Bo;Zhong Yuxu;Kong Dexin
我们以前报道过地高辛可以通过抑制DNA损伤修复（DDR）来增强DNA损伤剂阿霉素的抗肿瘤作用。地高辛的治疗窗很窄，多柔比星经常在肝脏和心脏等器官中引起毒性。因此，我们最近设计了一种含有地高辛和多柔比星的仿生无载体纳米颗粒系统，通过特异性靶向肿瘤细胞，进一步提高抗肿瘤疗效，同时减少副作用。在该系统中，将DDR抑制剂地高辛和DNA损伤剂阿霉素组合以配制无载体纳米颗粒（DDNP），其进一步包埋到NSCLC细胞系A549细胞膜包裹的框架中（称为DDMNP）。DDMNPs特异性内化到A549细胞中，但不内化到其他细胞如前列腺癌DU 145和巨噬细胞RAW 264.7细胞中。与地高辛和阿霉素的自由药物组合（DIG + DOX）或简单的DDNP相比，仿生DDMNP系统通过引起细胞凋亡和增强DNA损伤而显示出增强的协同治疗作用，这可能是由于DNA损伤标志物γ H2 AX和复制蛋白A（RPA）的表达增加，同时抑制了DDR蛋白的mRNA和蛋白表达。一致地，在斑马鱼和裸鼠A549异种移植模型中证实了更有效的体内抗肿瘤功效。此外，虽然游离药物组合（DIG + DOX）引起肝毒性，如组织学分析所示，但DDNP和仿生DDMNP没有，表明安全性提高。总之，通过仿生无载体纳米粒子共递送DDR抑制剂和DNA损伤剂可能成为癌症化疗的创新策略，同时需要更多的临床前和临床证据。
We previously reported that digoxin could enhance the antitumor effect of the DNA damaging agent doxorubicin by inhibiting DNA damage repair (DDR). Digoxin has a narrow therapeutic window, and doxorubicin often causes toxicity in organs such as the liver and heart. Therefore, we recently designed a biomimetic carrier-free nanoparticle system containing digoxin and doxorubicin to increase the antitumor efficacy further while reducing side effects, via specifically targeting tumor cells. In this system, the DDR inhibitor digoxin and the DNA damage agent doxorubicin were combined to formulate carrier-free nanoparticles (DDNPs), which were further embedded into the NSCLC cell line A549 cell membrane camouflaged framework (termed as DDMNPs). The DDMNPs were specifically internalized into A549 cells but not to other cells such as prostate cancer DU145 and macrophage RAW264.7 cells. Compared with the free drug combination of digoxin and doxorubicin (DIG + DOX) or simple DDNPs, the biomimetic DDMNP system displayed amplified synergistic therapeutic effects by causing cell apoptosis and enhancing DNA damage, probably due to the increased expression of DNA damage markers γH2AX and Replication protein A (RPA), and simultaneously suppressed mRNA and protein expression of DDR proteins. Consistently, more potentin vivoantitumor efficacy was demonstrated in zebrafish and nude mouse A549 xenograft models. Additionally, while the free drug combination (DIG + DOX) caused liver toxicity, as shown by histological analysis, DDNPs and biomimetic DDMNPs did not, suggesting improved safety. In conclusion, the codelivery of a DDR inhibitor and a DNA damaging agent via biomimetic carrier-free nanoparticles may become an innovative strategy for cancer chemotherapy, while more preclinical and clinical evidence is required.
登录
查看更多内容
DOI：
10.1038/nrc2607
发表时间：
2009-05
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
通讯作者：
--
影响因子：
51.1
作者：
Pujade-Lauraine, Eric;Ledermann, Jonathan A.;Pautier, Patricia
通讯作者：
Pautier, Patricia
DOI：
10.1038/s41571-018-0114-z
发表时间：
2019-03
期刊：
Nature reviews. Clinical oncology
影响因子：
--
作者：
Pilié PG;Tang C;Mills GB;Yap TA
通讯作者：
Yap TA
影响因子：
11.2
作者：
P. Vichi;S. Robison;T. Tritton
通讯作者：
P. Vichi;S. Robison;T. Tritton
具有高药物负载的智能阿霉素纳米颗粒，可增强化疗抗耐药性和癌症诊断
影响因子：
6.7
作者：
Yu, Caitong;Zhou, Mengjiao;Zhang, Xiaohong
通讯作者：
Zhang, Xiaohong