Lin Xi, Li Lian, Li Shujie, Li Qiuyi, Xie Dandan, Zhou Minglu, Huang Yuan
Key Laboratory of Drug Targeting and Drug Delivery System (Ministry of Education) West China School of Pharmacy Sichuan University No. 17, Block 3, South Renmin Road Chengdu 610041 P.R. China.
Adv Sci (Weinh). 2020 Dec 31;8(4):2002834. doi: 10.1002/advs.202002834. eCollection 2021 Feb.
Mitochondria are highly involved in the metastasis of cancer cells. However, low permeability of mitochondria impedes the entry of anti-cancer drugs. Here, a self-assembled nanoparticle platform is designed that not only targets the DNA-intercalating agent doxorubicin to mitochondria but also enhances the specific penetration by opening the mitochondrial permeability transition pores (MPTPs). With drastic improvement in mitochondrial uptake, the drug delivery system results in substantial mitochondrial impairment leading to amplified induction of apoptosis, depletion of energy supply, and inhibition of numerous metastasis-associated proteins. As a consequence, the drug delivery system significantly inhibits the orthotopic tumor growth, and suppressed the metastasis of cancer cells detached from primary tumors. Additionally, the nanoparticle exhibits a potent effect on eradicating the metastasis of disseminated tumor cell from blood to lung. The results show that strategies of targeting mitochondria and unlocking MPTP are feasible and beneficial to mitigate both tumorigenesis and metastasis.
线粒体在癌细胞转移过程中发挥着重要作用。然而，线粒体的低通透性阻碍了抗癌药物的进入。在此，设计了一种自组装纳米颗粒平台，它不仅能将DNA嵌入剂阿霉素靶向输送到线粒体，还能通过打开线粒体通透性转换孔（MPTP）增强特异性渗透。随着线粒体摄取的显著改善，该药物递送系统导致线粒体严重受损，进而放大了细胞凋亡的诱导、能量供应的消耗以及对多种转移相关蛋白的抑制。因此，该药物递送系统显著抑制原位肿瘤生长，并抑制原发肿瘤脱落癌细胞的转移。此外，纳米颗粒对消除从血液转移至肺部的播散肿瘤细胞的转移具有显著效果。结果表明，靶向线粒体和开启MPTP的策略对于减轻肿瘤发生和转移是可行且有益的。
