Biomimetic carrier-free nanoparticle delivers digoxin and doxorubicin to exhibit synergetic antitumor activity in vitro and in vivo

Abstract 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 potent in vivo antitumor 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.