Applied Materials Today
Fenton reaction-based nanomedicine in cancer chemodynamic and synergistic therapy
Graphical abstract
Introduction
Cancer is one of the leading causes of diseases-associated death in the world. In the past several decades, some cancer therapeutic methods, such as surgical therapy, radiotherapy, chemotherapy, immunotherapy, have been applied in clinical practice. Although tremendous efforts from different research fields have been made to campaign against cancer, it remains a lengthy process to win this batter due to the solid tumors' complicity and heterogeneity [1], [2], [3]. As by-products of cellular metabolism, reactive oxygen species (ROS) play a crucial role in cancer biology. ROS, including singlet oxygen (1O2), peroxide (O22−), superoxide (O2−), and hydroxyl radical (•OH), are derived from the incomplete reduction of oxygen (O2) in the electron transport chain of mitochondria during aerobic respiration [4], [5], [6], [7], [8], [9], [10]. In general, ROS functions as a double-edged sword in vivo. It can activate antitumorigenic pathways to induce cancer cell death and upregulate pro-tumorigenic signals to promote tumor proliferation [11], [12], [13]. Due to high ROS levels that can cause cancer cells killing effect, modulating the redox mechanisms in tumor cells has been recognized as an effective strategy to achieve potent cancer treatment [3,14]. Therefore, several effective cancer treatment strategies, such as photodynamic therapy (PDT) [15], sonodynamic therapy (SDT) [16], have been developed via the rational design of nanomaterials for ROS-augmented tumor inhibition. However, PDT, which employs photosensitizers (PSs) to transfer exciting energy to oxygen molecules to generate ROS, is limited by light penetration depth and tumor hypoxia [17]. SDT triggered by exogenous ultrasound stimulation is restricted to finite nearby oxygen molecules [18]. With a deeper understanding of tumor biology, especially tumor microenvironment (TME), some new cancer treatment strategies continue to be developed in recent years.
As is well known, TEM has unique biochemical features, such as mild acidity, low catalase activity, high level of glutathione (GSH), and overexpressed H2O2 (ranging from 100 μM to 1 mM) [19,20]. Meanwhile, it is a novel and attractive therapeutic concept that is utilizing the intrinsic biochemical features as endogenous stimuli to activate in situ chemical reactions of nanomedicines in the tumor site, where the low toxic substance can be transformed into highly toxic substances against tumors with high therapeutic efficacy and negligible side effects [21,22]. This TME-depending and toxic ROS-generating therapeutic modality are defined as chemodynamic therapy (CDT) by Shi group in 2016 (Fig. 1) [23]. In the related CDT research, nanocatalytic medicine is designed to be accumulated in the tumor site via the EPR effect. The as-prepared nanosystem can respond to the intratumoral H+ to release Fenton catalysts to convert low toxic H2O2 into highly toxic •OH via Fenton or Fenton-like reaction against tumors. This process is accompanied by the dramatic elevation of oxidation ability in cancer cells, which is desired for cell killing [24,25]. However, the direct introduction of free Fe2+ into bodies can't achieve expected therapeutic effects, owing to the non-specificity oxidative damage of free Fe2+ in noncancerous and cancer regions, hindering the efficiency of Fenton reaction in vivo [26], [27], [28]. Thus, numerous of nanocatalytic medicine with various specific structures and compositions, such as iron oxide nanoparticles (IONPs) [29], amorphous Fe0 nanoparticles [23], mesoporous organosilica nanoparticles (MONs)-based nanocatalysts [30], and metal-organic frameworks (MOFs)-based nanocatalysts [31], have been constructed to facilitate the Fenton reaction via utilizing the unique biochemical features of TME against tumors for cancer therapy [23,[32], [33], [34]].
Due to the unique pattern of highly toxic •OH production, CDT can conquer the significant obstacles of resisting hypoxia and limiting penetration depth confronted by PDT or SDT and avoiding the damage to healthy cells caused by chemotherapy radiotherapy [35]. It also should be noted that the oxidation capability of •OH (E (•OH/H2O) = 2.8 V) produced by Fenton reaction is more robust than that of 1O2 (1O2/H2O) = 2.17 V) generated by PDT or SDT [36]. However, finite H2O2 content and overexpressed GSH limit the therapeutic effect of classical Fenton reaction-based CDT to some extent. Therefore, a new modified Fenton reaction-based CDT has been proposed as a potential and alternative approach for combating cancer [22,35]. Besides, significant advances have also been achieved in CDT-mediated multimodal cooperative therapy in recent years, which can overcome the disadvantages of each of monotherapy and realize the conspicuous super-additive (namely “1 + 1 > 2”) therapeutic effects in cancer eradication [37], [38], [39], [40], [41], [42], [43], [44]. This review outlines Fenton reaction-based nanocatalytic medicine in CDT and corresponding synergistic therapy strategies (Fig. 2), which can be helpful to understand this new paradigm in cancer treatment, and anticipates the obstacles and challenges in the future development of CDT for clinical translation.
Section snippets
ROS in cancer therapy
Since ROS can serve as intracellular signaling molecules, which have been documented but remain controversial, tight regulation of ROS levels is crucial for cancer treatment. On the one hand, the moderate ROS levels contribute to protumorigenic signaling, the control of cell proliferation and differentiation, and adaptation to hypoxia. On the other hand, overexpressed ROS promotes antitumorigenic signaling and triggers cancer cell death induced by oxidative stress [45,46].
Classification and characteristics of Fenton reaction in CDT
The unique characteristics of TME (H2O2 over-expression and mild acidity) can trigger a Fenton reaction in the presence of Fenton catalysts. This specific Fenton reaction only inside tumor tissues can generate abundant toxic •OH locally to initiate pathologic effects, enabling tumor-specific treatment efficiency without significant side effects on normal tissues. The fast developments of intratumoral Fenton reactions in cancer therapy promote the emergence of versatile therapeutics.
CDT in synergistic cancer therapy
The spontaneous response of CDT has an excellent therapeutic effect. However, the complexity and heterogeneity of TME restrict the occurrence of Fenton or Fenton-like reactions to some extent. Thus, it is desired to integrate two or more types of single treatment modalities to promote the advantages and to overcome the intrinsic drawbacks of monotherapy, which can augment the therapeutic performance of combination therapy and result in a super-additive effect.
Conclusions and outlook
The unique features of ROS in biological systems have been driving researchers to design numerous nanomaterials for defecting cancer. Over the past several decades, ROS-mediated PDT and SDT have been widely exploited as a promising strategy for cancer cell killing and tumor eradication. The therapeutic efficacy is limited by low selectivity and potential toxicity of photosensitizer/sonosensitizer, tumor hypoxia, or limited light penetration depth. Fortunately, ROS-mediated CDT emerges as a new
Declaration of Competing Interest
The authors declare no competing financial interest.
Acknowledgments
This work is supported by The National Natural Science Foundation of China (81771976), National Key Research and Development Program of China (Grant 2018YFC1901202), Fundamental Research Funds for the Central Universities, and the joint fund of Southeast University and Nanjing Medical University.
References (167)
- et al.
Nanocatalysts-augmented Fenton chemical reaction for nanocatalytic tumor therapy
Biomaterials
(2019) - et al.
Metal sulfides as excellent co-catalysts for H2O2 decomposition in advanced oxidation processes
Chemistry
(2018) - et al.
Rerouting engineered metal-dependent shapes of mesoporous silica nanocontainers to biodegradable Janus-type (sphero-ellipsoid) nanoreactors for chemodynamic therapy
Chem. Eng. J.
(2019) - et al.
Mitochondria-derived ROS activate AMP-activated protein kinase (AMPK) indirectly
J. Biol. Chem.
(2018) - et al.
Structure and mechanisms of ROS generation by NADPH oxidases
Curr. Opin. Struc. Biol.
(2019) Toxicity of iron and hydrogen peroxide: the Fenton reaction
Toxicol. Lett.
(1995)- et al.
Nanomaterial-induced ferroptosis for cancer specific therapy
Coord. Chem. Rev.
(2019) - et al.
Multifunctional nanoplatform for photoacoustic imaging-guided combined therapy enhanced by CO induced ferroptosis
Biomaterials
(2019) - et al.
Advances in metal-induced oxidative stress and human disease
Toxicology
(2011) - et al.
Glutathione and redox signaling in substance abuse
Biomed. Pharmacother.
(2014)