ZIF8/Graphene Oxide Nanosheets for Combined Ion-Interference and Photothermal Therapy

Objectives: In this work, we designed a multifunctional nanoplatform (BSArGO@ZIF8 NSs) by in situ growth of metal-organic framework nanoparticles (ZIF-8 NPs) onto the graphene oxide (GO) nanosheets surface, ascorbic acid reduction, and BSA modification. BSArGO@ZIF-8 NSs were used to treat oral squamous cell carcinoma by the combination of Ion-interference and photothermal therapy.
Methods: ZIF8 NPs in situ grew on GO surface to form GO@ZIF8 NSs. BSArGO@ZIF8 NSs were prepared by ascorbic acid reduction and BSA modification. CCK8 analysis, live/dead staining, and flow cytometry were performed to confirm the lethality of BSArGO@ZIF8 NSs to cancer cells. Zn²⁺ and ROS staining were performed to confirm that BSArGO@ZIF8 NSs caused intracellular Zn²⁺ content and ROS level. Apoptosis staining and flow cytometry were performed to study Zn²⁺ mediated apoptosis. the whole transcriptome sequencing was used to accurately clarify the mechanism of BSArGO@ZIF8 NSs causing cancer cell death. Under 808n nm irradiation, ion-interference/photothermal combined therapy was studied in vitro and in vivo. The staining of H&E, TUNEL, Ki67, and CD31 was performed to evaluate the efficiency of BSArGO@ZIF8 NSs mediated cancer therapy.
Results: BSArGO@ZIF8 NSs caused the intracellular overload of Zn²⁺ and an increase of ROS and exerted a broad-spectrum lethality to different kinds of cancer cells. BSArGO@ZIF8 NSs can promote cell apoptosis by initiating bim (a pro-apoptotic protein)-mediated mitochondrial apoptotic events, up-regulating PUMA/NOXA expression, and down-regulating the level of Bid/p53AIP1. Meanwhile, Zn²⁺ overload triggers cellular dysfunction and mitochondria damage by activating the autophagy signaling pathways and disturbing the intracellular environmental homeostasis. Under NIR light irradiation, BSArGO@ZIF8 NSs led to effective apoptosis and inhibited cell proliferation and angiogenesis, bringing a higher efficacy in tumor suppression in vivo.
Conclusions: Combined with the photothermal effect of rGO, BSArGO@ZIF8 NSs mediated ion interference and photothermal combined therapy showed higher efficacy in tumor suppression in vivo. This designed Zn based multifunctional nanoplatform will allow promoting further the development of IIT and the corresponding combined cancer therapy strategy.