Background

Cancer has always been a serious threat to human life and health, which needs to be solved urgently. Although traditional therapeutic strategies including chemotherapy together, radiotherapy, and surgery (Peer et al. 2007) have demonstrated plenty of achievements, they are still limited in clinical applications due to drawbacks like multidrug resistant (MDR) effect, poor bioavailability, and non-specific biodistribution in the body (Yi et al. 2019; Yan et al. 2021). To improve the safety and effectiveness of tumor therapy, the development of a novel anticancer therapeutic strategy becomes one of the key issues. In recent years, new methods facilitated by using nanomaterials show great promises in anticancer treatment (Qian et al. 2017; Yan et al. 2018, 2020).

As a shining star among nanomaterials, graphene oxide-based nanomaterials have gained significant research interests globally ever since it was first demonstrated in the year of 2004 (Kakran et al. 2011). In 2008, Dai’s research team first demonstrated that polyethylene glycol (PEG)-GO can be used as a versatile platform for delivering anticancer drugs delivery. The investigation of graphene oxide-based nanomaterials has opened new perspectives for cancer treatment with improved therapeutic efficiency (Liu et al. 2008).

Graphene oxide-based nanomaterials, GO and rGO, have unique property including chemical and mechanical stability, two-dimensional structures, and biocompatibility. Moreover, they have a large and easy-to-modify surfaces that can be modified to link with epoxide hydroxyl, carboxyl, and hydroxy (–O–, –COOH, –OH) groups. These groups can be further used to change the surface characteristic of GO and provide attachment sites to various molecules, including protein, deoxyribonucleic acid (DNA), and ribonucleic acid (RNA) (Yang et al. 2010) designed Fe3O4 decorated poly (4-styrene sulfonate)-GO for MRI application by the high-temperature thermal decomposition method. The prepared functional GO exhibited good water solubility and excellent MRI effect. Zhang et al. (2013) report on the development of a two-dimensional nanomaterial GO-based T1 MRI CA. Compared with gadolinium diethylene triamine pentaacetate (Gd-DTPA), gadolinium-functionalized nanographene oxide (Gd-NGO) showed a much higher T1 relaxivity value (r1) and contrast of in vivo T1-weighted MRI. Moreover, Peng et al. (2012) developed a MnFe2O4 nanoparticle decorated-GO for T2-weighted MRI, which got a high T2 relaxivity value (r2) of 256.2 (mM)−1 s−1.

The combination of MRI and PTT is of great significance to realize simultaneous diagnosis and treatment. For instance, Meng et al. (2017) prepared nanoscaled metal–organic frames (NMOFs) composited GO and used it in tumor-guided PTT with MRI. Results revealed that the fabricated NMOFs/GO was effective in imaging-guided PTT for clinical antitumor applications. T1-weighted MRI-guided PTT was also adopted for tumor therapy (Zhang et al. 2015a, b, c). The author designed a BaGdF5 and PEG-modified GO, which exhibited excellent T1-weighted imaging and photothermal conversion performance. According to the obvious contrast between tumor tissue and normal tissue on the MRI, the location and size of the tumor can be clearly obtained. Then, the tumor area of the mice treated with GO/BaGdF5/PEG was irradiated by a near-infrared laser to produced significant heating to achieve the antitumor effect.

Fluorescence imaging

FLI is a non-invasive technique based on photons emitted by fluorescent probes (Baker and Baker 2010; Zhu et al. 2013; Tang et al. Biosafety

It is crucial to study the biosafety of graphene oxide-based nanomaterials in vitro and in vivo to determine whether they can be used as clinical candidates. So far, extensive studies have been illustrated the biotoxicity, immunological compatibility, immunological compatibility, and inflammatory responses of graphene oxide-based nanomaterials.

Biotoxicity

Graphene oxide-based nanomaterials show great potentials in cancer treatment due to outstanding properties such as surface properties, photothermal property, and pH sensitivity. However, researchers need to consider their biotoxicity as one of the primary issues (Wang et al. 2011). Most researches have indicated that the biological toxicity of graphene oxide mainly comes from its surface properties: charge, oxygen content, surface structure, lateral dimension, and corona effect. (Guo et al. 2014). Besides, other factors are involved in influencing biotoxicity: cell types, concentration, and detection methods (Gautam et al. Miyanda and Gautam, 2017).

It has been proven that graphene oxide-based nanocomposites show toxicity effects to both prokaryotic and eukaryotic cells. For toxicity to eukaryotic cells, numbers of mechanisms have been proposed, such as DNA and mitochondrial damage (Liu et al. 2013a, b, c), inflammatory responses (Orecchioni et al. 2016), autophagy (Huang et al. 2015), necrosis (Qu et al. 2013), and apoptosis (Li et al. 2012a, b). For toxicity to prokaryotic cells, Zou et al. (2016) summarized the mechanisms of the antimicrobial activities of graphene oxide-based nanomaterials, such as encapsulate and capture bacterial membranes. Furthermore, results of in vitro and in vivo experiments have shown that GO had obvious dose-dependent toxicity. In studying the toxicity of GO in mice, it was found that low-dose (0.1 mg) and medium-dose (0.25 mg) GO had almost no effect on mice. While when the dose reached 4 mg, it showed liver and lung damage (Wang et al. 2011). In addition, chromosomal aberrations and DNA damage induced by GO were also found (Durán et al. 2017).

Hemocompatibility

Hemocompatibility investigation is an important toxicity assessment of GO (Kiew et al. 2016). In general, fresh blood collected from healthy animals is applied for hemolytic analysis to evaluate hemocompatibility. The hemolytic properties of GO were usually caused due to the electrostatic interaction between the GO and membrane of red blood cell (RBC). However, proper surface modifications could improve the hemocompatibility of GO. For example, by adopting CS, the hemolytic activity of GO can be significantly eliminated (Wu et al. 2015).

Immunological compatibility

Immunological compatibility of GO is also considered as a factor of biosafety. It has been reported that the presence of GO could cause strong immunogenicity proved by a remarkable increase of tumor necrosis factor alpha (TNF-α), interleukin-1 (IL-1), and interleukin-6 (IL-6) (Zhi et al. 2013). Meanwhile, PVP-modified GO possesses better immunological compatibility.

Inflammatory responses

When macrophages play the role of unconventional immune defense, GO can be eliminated or cause inflammation before reaching the target. Yue et al. (2012) found that IL-6, TNF-α, monocyte chemotactic protein 1 (MCP-1), interleukin-12 (IL-12), and interferon γ (IFN-γ) can be increased significantly in the presence of GO, leading to serious inflammatory responses. Ma et al. (2015) reported GO can induce more inflammatory cytokines by interacting with toll-like receptors to activate the NF-kappaB (NF-kB) pathway. Meanwhile, some studies showed that functionalized NGOs could avoid inflammatory responses by macrophages via weakening the opsonin–protein interaction (Kiew et al. 2016).

Conclusion

This review aims to investigate the applications of graphene oxide-based nanomaterials (e.g., GO and rGO) in cancer therapy including drug/gene delivery, phototherapy, bioimaging. In terms of drug and gene delivery, compared with other drug delivery systems, graphene oxide-based nanomaterials can obviously display high drug loading rate, targeting effect, increasing the sensitivity of chemotherapy drugs/genes. For the application of phototherapy, the combination of graphene oxide-based nanomaterials with PTT to achieve tumor elimination through the photothermal effect of GO. PDT based on graphene oxide-based nanomaterials can increase the water solubility of hydrophobic PSs and selectively deliver PS to cancer cells via the EPR effect. Meanwhile, the therapeutic diagnosis platform assembled by graphene oxide-based nanomaterials is applied to the early diagnosis and treatment of cancer. Besides, to obtain the best cancer treatment effect, new treatment strategies have been proposed such as PTT-PDT, chemo-PTT, and chemo-PDT.

A review of current literature has revealed the majority of present studies demonstrate that graphene oxide-based nanomaterials hold a bright future in nanomedicine. This review not only summarizes the excellent achievements in the last decades, but also pays particular attentions to the latest achievements in 2 years. Moreover, this review represents a comprehensive summary of all the aspects of applying graphene oxide-based nanomaterials in cancer treatment. Overall, this review can help readers achieve comprehensive understanding of the application of graphene oxide-based nanomaterials in tumor treatment and grasp the latest research achievements, thus inspiring novel research ideas and making contribution to the research field of graphene oxide-based nanomaterials for antitumor therapy. Unfortunately, there still exist some requirements to address the remaining challenges. One of the concerns for the challenge is the toxicity of graphene oxide-based nanomaterials. Although a large number of studies have been conducted to confirm the in vitro and in vivo toxicity of graphene oxide-based nanomaterials and its derivatives, the potential nanotoxicity requires further in-depth investigations. For in vitro toxicity, it is very important to understand its mechanism, especially the cellular uptake mechanism of graphene oxide-based nanomaterials. For in vivo toxicity, it is necessary to study the absorption, distribution, metabolism, and excretion in vivo. Furthermore, how to properly design graphene oxide-based nanomaterials to achieve the desired therapeutic effect is a critical issue. On the one hand, to diagnose and treat tumors, drugs or other functional agents need to be successfully delivered to tumor tissues and retained for a long time. Graphene oxide-based nanomaterials need to be designed to a suitable size to avoid the endoplasmic reticulation of large-size nanomaterials and the rapid clearance of ultra-small nanomaterials and to effectively passively target the tumor site. On the other hand, according to the receptors overexpressed on the tumor cell membrane to ensure the effective accumulation and retention of graphene oxide-based nanomaterials in the tumor. Endogenous and exogenous stimuli should also be fully utilized to realize the intelligent regulation of tumor nanoplatforms. Besides, many shortcomings in the design of graphene oxide-based nanomaterials as the multifunctional platform should be avoided, including complex design, cumbersome synthesis, low integration efficiency, lack of synergy, and uncertain biological responses.

In conclusion, graphene oxide-based nanomaterials have brought many surprises and challenges. In the near future graphene oxide-based nanomaterials will arouse ultimate benefits for human diseases treatment, especially for cancer treatment.