In gynecological malignancies, ovarian cancer is the one of the leading causes of death.1,2 Although combination of platinum and a taxane-containing agent remains the major treatment method after surgical resection, most patients ultimately succumb to the disorder because of the limited effects of the treatment on cancer growth, relapse, and drug resistance.3,4 Consequently, there is an urgent need to exploit more effective treatment means to treat ovarian cancer and delay or prevent recurrences.5
Compared with traditional treatments, nanomaterials offer new opportunities for the development of diagnostic and therapeutic tools for cancer and other diseases.6–8 Ag, Au, ZnO, TiO2, As2O3, graphene oxide-silver nanoparticle, and iron core-gold shell nanoparticles have been reported to cause the apoptosis of cancer cells.9–13 It was shown that some nanomaterials may have anticancer properties, mainly due to toxicity of the nanomaterials, but there is still a lack of nanomaterials that selectively distinguish cancer cells from normal cells.
More and more evidences indicated that cancer progression is closely related to the tumour microenvironment, including the extracellular matrix (ECM) deregulation, blood vessels expanding and immune response suppression.14 Matrix metalloproteinases (MMPs) are a family of enzymes, have the ability to proteolytically degrade various components of ECM, participate in remodeling of basement membranes and contributed to angiogenesis.14 The decrease of MMPs expression or enzymatic activities is considered to be the main factor for the inhibition potential of migration and angiogenesis. Angiogenesis, supplies oxygen and nutrients to actively proliferating cancer cells, provides advantages for cancer cells growth, invasion and metastasis.15, 16 Numerous signalling molecules and pathways associated with angiogenic responses in the tumour microenvironment, play major roles in cancer cell growth and metastasis.17, 18 Therefore, developing MMPs and angiogenesis inhibitor has become an effective tumor treatment strategy. Most current reports focus on targeting the vascular endothelial growth factor (VEGF). For example, gadolinium metallofullerenol nanoparticles, AgNPs,19 and hollow mesoporous carbon nanocapsules (HMCNs)20 have been reported to regulate tumour angiogenesis by VEGF pathway. We found that Fe-MIL-101 have an anti-angiogenesis potential utility by reducing MMP-2/9 expression. 21
In addition, the regulation of cytoskeleton plays a key role in the process of metastasis in cancer cells.22 Actin, as an important part of cytoskeleton, has the function of maintaining the communication between cytoplasmic proteins and transmembrane, keeping mechanical strength, and regulating cells locomotion.22 Recently, several studies have reported the effects of some nanomaterials on actin cytoskeleton in cancer cells. For example, carbon nanomaterial,23 curcumin analog MHMD,24 grapheneoxide nanosheets,25 AgNPs,26 and ZnONPs 27 affected F-actin cytoskeleton through targeting or disruption of F-actin. It has been reported the metal-organic frameworks (IRMOF-3) possesses the ability to disrupt F-actin and tubulin, blocking the rat pheochromocytoma cell division.28 Recently, we found Cu-MOF has an intrinsic activity of protease-mimicking 29 and disrupts of F-actin in ovarian cancer cells, leading the mitotic catastrophe.30
Carbon quantum dots (CQDs) are currently eliciting much attention in cancer therapy due to outstanding properties including biocompatibility, low cytotoxicity, water solubility and unique photoluminescence.31 CQDs and CQDs-based composites can be used for anti-cancer by phototherapy and radiotherapy. For instance, CQDs inhibited human breast cancer cells MCF-7 and MDA-MB-231 by photodynamic therapy triggering the formation of singlet oxygen species.32 It was reported CQDs could be used as photosensitizers to destroy buried tumors in photodynamic therapy. C-Ag-PEG CQDs inhibited Du145 cells by free radicals in radiotherapy, which reduced the damage of normal cells and increased therapeutic selectivity.33 It has been reported CQDs can selectively target cancer cells through regulated the expression of major angiogenic cytokines, such as VEGF, FGF, and VEGFR2.34 The results were shown that the angiogenesis inhibition rate of 100 µg CQDs was less than 40%. It is an effective strategy for tumor therapy to develop carbon quantum dot composite materials, making use of its synergistic effect to improve the anti-angiogenesis activity.
Cu2O NPs has been extensively researched to elucidate their significance in cancer therapy. Cu2O NPs significantly reduce the growth and metastasis of melanoma, improve the viability of tumor-bearing mice, and induce the mitochondrion-mediated apoptosis of cancer cells.35 Cu2O NPs was more sensitive to rapidly proliferating HeLa cancer cells than normal human kidney 293T cells, indicating Cu2O NPs exert distinct effects on different cells.36 Since one of the biggest challenges of chemotherapy is that chemotherapy drugs do not effectively distinguish between tumor and normal cells, differential cytotoxicity is very important.36
Gene expression experiments, as a method for detection of disease markers, has been used to assessment the toxicity mechanism of nanomaterials.37 For example, Ag nanoparticles involved regulating gene expression, including oxidative phosphorylation gene, protein synthesis gene, vascular endothelial growth factor-A (VEGFA) gene and fibroblast growth factor2 (FGF2) gene in different cell lines.38, 39 Single-walled carbon nanotubes also regulated gene expression of relative root growth, influence.40 Melittin-loaded ZIF8 nanoparticles was found to induce A549 cells apoptosis through regulating the expression of 3383 genes.41 Recently, we reported that Cu-MOF (HKUST-1) induced mitotic catastrophe through destruction of actin cytoskeleton and changes of gene expression in SKOV3 cells. 30
On the other hand, the proteases naturally expressed by living organisms participate in all stages of tumor progression. In our previous study, we found that the CQDs/Cu2O composite possessed an intrinsic protease-mimicking activity for hydrolyzing proteins under physiological conditions, ultimately exhibiting a surprisingly higher catalytic activity than Cu2O and CQDs.42 Based on the above findings, we investigated the inhibitory mechanism of CQDs/Cu2O composite on human ovarian cancer (SKOV3) cells. It will be attractive to elucidative the potential roles of the CQDs/Cu2O composite in the regulation of cancer-related proteins. Furthermore, only a few nanoparticles have been reported to interact with the tumour microenvironment. As far as we know, this is the first attempt to reveal CQDs/Cu2O composite mediates tumor microenvironment and cytoskeleton.