Abstract
Hypoxia, a hallmark of cancer, compromises the efficacy of chemotherapy and other oxygen-dependent modalities (e.g., sonodynamic therapy). For monotherapy, this effect becomes more pronounced because of drug resistance and an adaptive tumor microenvironment. To overcome this, here, we reported metal–organic framework (MOF)-based nanotherapeutics (DOX/Ce6@ZIF-8@PDA) to simultaneously deliver Ce6 and doxorubicin for synergistic sonodynamic/chemotherapy. Notably, O2 storage ability of MOFs relieves tumor hypoxia to sensitize the tumor to sonodynamic therapy and chemotherapy. Moreover, polydopamine (PDA) promotes endocytosis and enhances intracellular drug concentration. The pH-responsive property of MOFs enables controlled drug release. The in vitro and in vivo results validate the impressive tumor inhibition, implying the potential of this combination therapy for cancer treatment.
Highlights
Hydrogen peroxide (H2O2, 30%), and zinc nitrate hexahydrate (≥98%) were purchased from Shanghai Aladdin Biochemical Technology Co., Ltd., Zn(NO3)2·6H2O), 2methylimidazole (98%, C4H6N2, 2-MI), doxorubicin (C27H29NO11, DOX), Ce6, 4,6-diamino-2-phenyl indole (DAPI), and MTT assay, were purchased from Thermo Fisher Co., Ltd.; the hypoxia/oxidative stress detection kit was obtained from Enzo Life Sciences, and the annexin V-FITC/PI double staining apoptosis detection kit was purchased from Beyotime Biotechnology Co., Ltd
DOX/zeolitic imidazolate frameworks (ZIFs)-8 crystals doped with DOX were constructed via an ion doping technology from previous reports
The DOX loading detection was shown by TGA, suggesting a sharp weight loss in DOX/ZIF-8 compared to ZIF-8 between 300 and 450°C, which was due to the DOX decomposition (Figure 1B)
Summary
The mortality rate of cancer has decreased over the past decade as reported by many studies. To cause damage or death of tumor cells, reactive oxygen species (ROS) have proved to be a reliable mechanism, which have been studied by many research groups. As the most widespread components in ROS, O2 and OH are effective in hampering tumor cells and damaging the tumor microenvironment. It has been reported that cancer therapies mediated by ROS can concentrate different redox states and cause more damage to cancer cells than normal cells, which endows them to be competitive in universal cancer treatments (Zhou et al, 2016). Among most accepted tumor therapies, Ce6 is expected to provide singlet oxygen (1O2) with O2 with an ultrasonic wave; the generated 1O2 is able to induce cell apoptosis.
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