- Nano Review
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Tuning the Toxicity of Reactive Oxygen Species into Advanced Tumor Therapy
Nanoscale Research Letters volume 16, Article number: 142 (2021)
The biological functions and toxic effects of reactive oxygen species (ROS) are generally entangled. A large amount of ROS may cause oxidative damage to cell biomolecules, leading to cell death. Tumor treatment can be carried out by using the toxicity of ROS, and various nanosystems related to ROS have been designed. In fact, the level of active oxygen in the biological microenvironment can be regulated in advanced therapeutics via designed nanoscale engineering, which can open up a new direction of treatment with specific simplicity. In this progress report, the authors first introduced how ROS causes cell death. Then, recent studies on converting the inherent toxicity from ROS into advanced treatment tools are highlighted.
Reactive oxygen species (ROS) are chemically active oxygen-containing atoms or groups, including singlet oxygen (1O2), superoxide anion (O2-), hydroxyl radical (·OH) and hydrogen peroxide (H2O2) [1,2,3,4]. Mitochondria is the main place for the generation of ROS in the cell, mainly through the electron transport chain, such as O2-·, ·OH and 1O2 are all by-products of aerobic metabolism . In most cells, more than 90% of the oxygen is consumed in the mitochondria, and 2% of the oxygen is converted into oxygen free radicals in the inner mitochondrial membrane and matrix [5, 6]. ROS has vital function in maintaining tissue homeostasis,regulating signal transduction and differentiation, and promoting cell damage and death. The level of ROS is controlled by the cellular antioxidant defense system [7,8,9,10].
ROS is the main molecule produced during oxidative stress in the body, and has been considered an important factor in tumor occurrence, development and recurrence . ROS include groups with unpaired electrons containing oxygen atoms and excessive ROS can damage biological macromolecules such as DNA and proteins in tissues. The increase of ROS will increase the mutation rate and promote the transformation of normal cells into tumor cells. ROS can also promote the stability of important signal molecules that drive tumorigenesis and progression. That is to say, ROS are not only a factor of tumor production, but also a factor of tumor deterioration. However, the increase of ROS in tumor cells can cause cell death, which can inhibit the further growth of tumor. Taken together, ROS can play multifaceted roles in tumor [12, 13]. Both detrimental and beneficial effects were found for ROS-mediated mechanisms with varying success [14,15,16]. The past decades have witnessed a tremendous growth of ROS-related nanotheranostics which are emerging as an important direction to future nanomedicine implicating a close crosstalk between multidisciplinary fields [17, 18]. To this end, it is important to decipher the logic between ROS generation and elimination to revolutionize the design considerations. In this progress report, we first provide the biological effects of ROS. Then, we discuss anti-tumor strategies based on ROS. Among them, we highlight recent studies for using ROS toxicity as a highly effective therapeutic tool for tumors (Fig. 1).
Fight Fire with Fire
ROS has been reported to be associated with cancer development and cancer cell death. Once the toxicity of ROS can be controlled well, applying ROS-related nanomedicines seems to be a promising approach to tumor therapeutic applications [7, 19, 20]. First, a large number of studies of the mechanism toxicity of ROS have provided a strong foundation for the development of methods for the transformation of toxicity to therapeutic effects [5, 6]. Moreover, from a practical perspective, many scientists have already demonstrated the feasibility of modification of nanomedicines to alter their physicochemical properties, enabling the precise control of ROS level at specific sites. Therefore, ROS-related nanomedicines have the immense potential to be an independent therapeutic tool. Indeed, some proof-of-concept studies have already specifically addressed this potential.
ROS promoted tumor development by inducing DNA mutation and genomic instability or as a signal molecule, accelerating tumor cell proliferation, survival and metastasis. However, excessive ROS enhance cellular oxidative stress, resulting in DNA, protein or lipid damage, and lead to cell apoptosis or necrosis [21, 22]. Therefore, boosting ROS in tumor cells through nanomedicines has been applied to the treatment of clinical cancer. In the following sections, we will survey the approaches enabling to increasing the intracellular ROS level, including photodynamic therapy (PDT), chemodynamic therapy (CDT) and radiation therapy (RT) in cancer therapy, thus facilitating the future development of new strategies to overcome the limitations of current ROS-based cancer therapies.
In a typical PDT system, photosensitizers (PSs), light and oxygen are the three essential components of PDT. The PS is transformed from its ground state to its triplet excited state through a short-lived singlet state as a result of excitation with light of a specific wavelength, and lead to generate excess cytotoxic ROS, then the ROS ultimately induces the regression of targeted lesions [23,24,25]. Figure 2 shows the mechanisms of PDT: In type I mechanisms, the PS reacts directly with an organic molecule in a cellular microenvironment, acquiring a hydrogen atom or electron to form a radical, leading to the production of ROS and macromolecule degradation, which is cytotoxic to the cell . In type II mechanisms, the PS in triplet state can either decay radiation lessly to the ground state or transfer its energy to molecular oxygen, which is unique in being a triplet in its ground state, leading to the formation of cytotoxic ROS, such as singlet oxygen (1O2). Unfortunately, owing to weak light absorption in the optical transparent window of biological tissues, most available PSs such as photofrin exhibit low1O2 quantum yields when excited by the light within the phototherapeutic window . Furthermore, the application of PDT has been limited by the poor bioavailability of the PSs, and low levels of oxygen in tumors can further decrease 1O2 production [27, 28]. Therefore, the design and exploitation of suitable PSs plays a vital role in promoting the development of PDT. Nanomaterials as a promising technique for PDT that can overcome most of the limitations of traditional PSs. This section combs the recent examples of that increase the level of intracellular ROS to enhance PDT, including various types of nanomaterials.
Black phosphorous nanosheets (BP NSs) with unique energy-band structures generate 1O2 under 660 nm near-infrared (NIR) light irradiation; therefore, they can be developed as highly effective PSs for PDT. Furthermore, studies have shown that the BP NSs can be degraded and have good biosafety performance  (Fig. 3a). Zhang et al. designed the BP-PEI/AuNPs hybrid nanosheet, which hybridized BP NSs employed as two-dimension (2D) inorganic PSs with gold nanoparticles (AuNPs) through polyetherimide (PEI). The significantly improved PDT effects of BP-PEI/AuNPs nanosheet resulted in the effective inhibition of the tumor growth both in vitro and in vivo (Fig. 3b) . Yang et al. successfully developed, BP quantum dots (BPQDs) and investigated their potential to serve as PDT agents. The BPQDs showed good stability in physiological medium and no observable toxicity after PEG conjugation. In addition, the BPQDs could effectively generate 1O2 under light irradiation. Both in vitro and in vivo studies demonstrated that the BPQDs exhibited excellent antitumor efficiency through the PDT (Fig. 3c) . Guo et al. reported a new class of multimodal therapeutic system based on BP NSs. Using DOX as a modal drug, BP possessed extremely higher drug loading capacity for DOX. Under near-infrared light, BP NSs can effectively generate 1O2 under NIR light irradiation. The intrinsic properties of BP NSs allowed them to simultaneously serve as both effcient PDT and PTT agents (Fig. 3d) .
Gold-based nanoparticles, have also been extensively studied for the application in PDT . Hwang et al. have presented the first literature example of nanomaterials-mediated PDT and demonstrated that upon NIR light irradiation, Au NRs can mediate PDT effects to completely destruct tumor in mice in the absence of additional organic photosensitizers (Fig. 4a) . Chen et al. designed aggregation‐induced emission gold clustoluminogens (AIE‐Au) to achieve efficient low‐dose X‐ray‐induced PDT (X‐PDT) with negligible side effects. X‐ray‐induced luminescence excited the conjugated photosensitizers, resulting in a PDT effect. The in vitro and in vivo experiments demonstrated that AIE‐Au effectively triggered the generation of 1O2 with an order‐of‐magnitude reduction in the X‐ray dose, enabling highly effective cancer treatment (Fig. 4b) . Jiang et al. developed the dihydrolipoic acid coated AuNCs (AuNC@DHLA) as PSs for efficient in vivo PDT. In contrast to the 1O2 (type II) mechanism of most conventional PSs, the photochemical mechanism of AuNC@DHLA involved the type I process. With AuNC@DHLA as the PSs, highly efficient in vivo PDT has been achieved (Fig. 4c) .
Although PDT has been applied clinically in recent years, it has not yet become a first-line treatment. It largely depends on the complex photosensitivity of PDT, which requires fine coordination between light, PS and oxygen (O2), which greatly limits the efficacy of PDT. In recent years, in order to improve the efficiency of PDT-mediated ROS generation, many methods have been developed, such as the use of new nanomaterials as light sensors to increase the depth of light penetration, and the use of nano-drug complexes as O2 supply systems to solve tumor tissues. However, the relationship between the retention time and spatial distribution of the oxygen provided by the nanosystem and the effectiveness of the nanosystem to enhance the anti-tumor effect needs further study.
Chemodynamic therapy (CDT) is an emerging cancer treatment method that uses the Fenton/Fenton-like reaction between metals and peroxides to generate highly reactive hydroxyl radicals (·OH) to achieve efficient tumor cell killing [37,38,39,40,41,42,43,44,45,46,47]. At present, the main method to achieve CDT is to deliver Fenton-active transition metal ions, thereby triggering the conversion of intracellular H2O2 to ·OH that to induce oxidative stress and subsequent cancer cell death through the oxidation of various biomolecules such as DNA and proteins [13, 16, 46,47,48,49,50,51,52,53]. The Fenton reaction has been written as Eqs. (1) and (2) .
The Fenton reaction is a process in which H2O2 reacts with ferrous ions to produce ·OH with strong oxidizing properties. Since the content of H2O2 in tumors is significantly higher than that in normal tissues, the generation of ·OH based on Fenton reaction is a preferred solution for the use of ROS to achieve selective tumor therapy; the effective and specific transport of ferrous ions to the tumor sites has become a research hotspot. Benefiting from the weak acid microenvironment characteristics of tumor, acid-sensitive iron-based nanomaterials can achieve selective release of ferrous ions at tumor sites, which is expected to achieve efficient and specific treatment of tumors.
To this end, Hou et al. developed a switchable MRI-guided cancer therapeutic agent based on ROS generation by Fe5C2@Fe3O4 NPs. The Fe5C2@Fe3O4 NPs are pH-sensitive, releasing ferrous ions in acidic tumor environments, and the discharged Fe2+ ions disproportionate the H2O2 that is overproduced at tumor sites to generate ·OH for effective tumor therapy (Fig. 5a) . Moreover, they have high magnetic properties, which are beneficial as they allow visualization of tumor aggregation through magnetic targeting and T2-weighted MRI. The effective tumor orientation and ROS generation were confirmed through both in vitro and in vivo experiments, which showed excellent therapeutic efficacy with low toxicity. In addition, the dissolution of Fe5C2@Fe3O4 NPs in the low-pH region reduces the T2 signal on MRI, and the release of ferrous ions raises the T1 signal, providing an MRI-supervised tumor therapy. These Fe5C2@Fe3O4 NPs are the pioneering paradigm of the application of iron carbide for tumor regression based on the selective catalysis of the Fenton reaction without the need for external energy input, providing a visible strategy for efficient and specific tumor therapy (Fig. 5b). In another example, Shi et al. explored an iron-containing metal–organic framework [MOF(Fe)] nanocatalyst as a peroxidase mimic is used to catalyze the generation of highly oxidizing ·OH radicals specifically within cancer cells, while chloroquine is applied to deacidify lysosomes and inhibit autophagy, cutting off the self-protection pathway under severe oxidative stress(Fig. 5c). Cancer cells fail to extract their components to detoxicate and strengthen themselves, finally succumbing to the ROS-induced oxidative damage during nanocatalytic therapy. Both in vitro and in vivo results demonstrated that such a combinational therapeutic approach results in remarkable antineoplastic effects, which may be hopefully to the design of treatment regimens in the future .
Apart from the production of ROS mediated by iron ions or iron based NPs, other metal ions, such as Mn2+, Cu2+, Ag+ and Pt2+, as well as their corresponding NPs, also show a Fenton-like activity [56,57,58,59,60,61,62,63,64]. Zhang et al. reported a copper metal–organic framework nanoparticles (Cu-MOF NPs) that copper clusters bridged by organic ligands loaded with sonosensitizers chlorin e6 (Ce6), which show good tumor accumulation, on-demand release numerous Cu2+ and Ce6 in responding to hypoxia TME, achieving glutathione (GSH)-depleted chemodynamic/sonodynamic therapy (CDT/SDT) (Fig. 5d) . In detail, the large size Cu-MOF NPs were effectively accumulated in the tumor via enhanced permeability and retention effect (EPR), and the hypoxia TME triggered the degradation of Cu-MOF NPs to release the Cu2+ and Ce6 and deep tumor penetration. The redox between free Cu2+ and intracellular high-level GSH, resulting in GSH depletion and reducing Cu2+ to Cu+. The Cu+ catalytic Fenton-like reaction shows a high catalytic activity and specificity in weakly acidic TME, which exhibited cytotoxicity to cancer cells. The GSH depletion and Ce6-mediated SDT further enhanced therapy efficiency. In vivo results showed the Cu-MOF NPs selectively and effectively killed cancer with high specificity and minimal invasivenes.
In recent years, CDT has made rapid progress in the field of tumor therapy, but there are still some challenges in the process of clinical transformation. For example, a series of challenges such as the mass repeatable synthesis of nanomaterials, the biosafety of nanomaterials, the evaluation criteria for the therapeutic effects of nanomaterials and the deeper biological principles, still require the concerted efforts of researchers from multiple disciplines to solve.
Radiation therapy (RT) is one of the most widely used methods in the treatment of cancer and plays a very important role in the treatment of cancer . RT, takes advantage of high-intensity ionizing radiation to suppress tumor proliferation with no depth restriction, during which it can induce DNA double-strand damage by generating considerable cytotoxic reactive oxygen species (ROS) produced by the ionization of surrounding water [66,67,68,69]. Therefore, to enhance ionizing radiation-induced cellular damage during radiotherapy, adequate ROS generation is essential to induce DNA double strand damage by reacting with DNA and greatly suppressing reconstruction of the broken double-stranded DNA . RT mainly uses ionizing radiation to irradiate tumor tissues to destroy the DNA of cancer cells by generating large amounts of cytotoxic reactive oxygen (ROS) . Ionization can cause atomic and molecular bonds to break, and DNA double-strand breaks are currently believed to be the main cause of cell death. However, some types of tumors or even intratumoral areas may be less sensitive to the cancer-killing effects of RT, due to mechanisms such as hypoxia during treatment and accelerated tumor cell reproliferation, which may lead to the aggregation of tumor cells that survive RT. Liu et al. developed the PFC@PLGA-RBCM NPs, in which the PFC core can dissolve large amounts of oxygen (O2) and the red-blood-cell membrane (RBCM) coating would enable greatly extend blood circulation for those nanoparticles. PFC@PLGA-RBCM NPs could effectively deliver O2 to the tumor after intravenous administration, thus greatly relieved tumor hypoxia and significantly enhanced treatment efficacy of RT (Fig. 6a) . Zhao et al. designed a GdW10@CS NPs for enhanced radiosensitization of RT in hypoxic tumors. The GdW10@CS NPs simultaneously utilizes the GdW10@CS as an external radiosensitizer to deposit radiation dosage and obliterate the intracellular GSH for more effective ROS generation. and HIF-1α siRNA as an internal stimulation method to inhibit double-stranded DNA repair to realize a radiosensitization effect of radiotherapy. the HIF-1α siRNA as an internal stimulus to inhibit double-stranded DNA repair and achieve radiosensitizer effects of RT(Fig. 6b) .
In order to enhance the cell damage induced by ionizing radiation in radiotherapy, it is essential to be able to generate enough ROS, which can induce DNA double-strand damage by reacting with DNA and greatly inhibit the remodeling of broken double-stranded DNA [74,75,76]. Recent studies have shown that increasing ROS level in tumor cells during RT can significantly improve RT efficiency and reduce radiotherapy dose, thus reducing non-selective killing of normal cells and serious systemic side effects on bystander organs. For instance, Tang et al. developed a mitochondrial targeting, Gd-doped titanium dioxide nanosensitizer called TiO2 (Gd)-TPP NPs for effective RT. Because the nanosensitizer has a large photoelectric cross section for X-rays, it can effectively produce ROS. The experimental results demonstrated that mitochondria-targeted nanosensitizers could significantly reduce the treatment dose and enhance the anti-tumor efficacy. This strategy may provide an effective and universal method to improve tumor radiosensitivity in future clinical cancer treatment (Fig. 6c) . Zhan et al. constructed a nano-coordination platform (NP@PVP) for bismuth nitrate and cisplatin precursors, namely a radiosensitizer. Bismuth in NP@PVP can sensitize RT by increasing the production of ROS and enhancing DNA damage after X-ray irradiation in tumor cells. NP@PVP had higher sensitization enhancement ratio (SER was 2.29) and better tumor ablation ability in compared with cisplatin (SER was 1.78) (Fig. 6d) .
Consequently, many studies have shown that the strategy of nanomedicine mediated ROS generation to achieve RT sensitization has great anti-cancer potential in RT, and has a good clinical application prospect. With the development of tumor molecular biology, the research and understanding of nanomedicine radiotherapy sensitization should go deep into molecular biology and gene level, and then a more essential and universal explanation mechanism of radiotherapy sensitization should be proposed. Therefore, it is necessary to strengthen the research on the mechanism of radiotherapy sensitization based on nanomaterials that promote the production of reactive oxygen species. This can not only clarify the radiosensitization mechanism of nanomaterials, and provide a basis for its application in the biological field; it also helps to further understand the interaction between nanomedicine, high-energy rays and biological tissues, thereby improving the structure and performance of nanomedicine. Expanding the scope of application, discovering new application areas, reducing toxic and side effects, etc. have guiding significance.
Conclusions and Outlook
This review aims to reveal and resolve the therapeutic effects of toxicity caused by ROS. In order to promote the shift in the role of reactive oxygen species from pathogenic factors to therapeutic factors, and facilitate successful therapeutic conversion, we should consider the principle of its toxicity and design ROS-related nanosystems.
ROS played an important role in the process of life, and high levels of ROS can cause oxidative damage to cell biomolecules, leading to cell death. We can use its toxicity to treat according to its mechanism of action to achieve the effect of “like cures like”. Therefore, ROS-based tumor treatment strategies show great promise. In recent years, there have been many studies devoted to the development of integrated ROS-regulation nanomaterials and many strategies have been developed to solve the existing problems in redox modulation therapy. This mini-review summarized the development and application of various ROS-related nanosystems for tumor treatment in recent years, involves ROS-induced toxicity treatment, and proposes some basic and key principles for the design of ROS-related nanosystems. Although the development of ROS-regulating therapy has made significant progress in recent years, the design of ROS-related nanosystems is still in its infancy, and there are still many challenges to be solved. PDT uses photosensitizers to generate ROS to kill tumor cells under light activation. However, the tumor hypoxia and limited light penetration depth limit its development. Compared with PDT, CDT is an emerging treatment strategy that uses biochemical reactions to produce ROS to kill tumor cells, which depends on neither molecular oxygen (O2) nor external light source, enabling chemodynamic therapy to avoid the major shortcomings of photodynamic therapy [79,80,81,82,83,84,85,86,87]. Despite its great therapeutic potential, CDT technology remains in its infancy. RT is the main treatment for various types of cancers clinically, and up to 50% of cancer patients receive this treatment modality. RT can effectively kill cancer cells by destroying the DNA double strand, but the self-repair mechanism of DNA in cancer cells highly limits its therapeutic effect. In addition, the insensitivity of hypoxic tumors to RT and the inevitable side effects at therapeutic doses also limit its efficacy.8 10 Meanwhile, normal tissues can also be injured like cancerous tissues because of non-selective absorption of X-rays. Thence, there are major problems caused by RT that need to be overcome with great efforts. High-efficiency radiosensitizers are important factors for improving RT efficacy, and it is very important to design new effective radiosensitizers for enhancing the absorption of X-rays, thereby achieving an effective therapeutic effect below the safe dose.
Generally, only PDT or CDT, RT treatment can not completely eliminate tumors, especially for metastatic tumors. It is possible to develop intelligent nanomedicines that can be used in synergy with multiple treatment methods, and can achieve synergistic treatment effects.As a whole, based on our growing understanding of ROS and the development of nanomaterials, undoubtedly, there are sustained discoveries of novel ROS-related nanosystems that are beneficial, andmay continuously lead to advanced therapeutics. In the future, researchers still need to continue to develop intelligent nano-reactive oxygen-related nanomaterials to selectively amplify the oxidative stress in tumor cells that can induce tumor cell death.
Availability of data and materials
Reactive oxygen species
- 1O2 :
- H2O2 :
- O2 :
Yu Z et al (2016) A nuclear targeted dual-photosensitizer for drug-resistant cancer therapy with NIR activated multiple ROS. Chem Sci 7(7):4237–4244
Forman HJ, Ursini F, Maiorino M (2014) An overview of mechanisms of redox signaling. J Mol Cell Cardiol 73:2–9
Flannagan RS, Cosio G, Grinstein S (2009) Antimicrobial mechanisms of phagocytes and bacterial evasion strategies. Nat Rev Microbiol 7(5):355–366
Lam PL et al (2020) The role of reactive oxygen species in the biological activity of antimicrobial agents: an updated mini review. Chem Biol Interact 320:109023
Harris IS, DeNicola GM (2020) The complex interplay between antioxidants and ROS in cancer. Trends Cell Biol 30(6):440–451
Perillo B et al (2020) ROS in cancer therapy: the bright side of the moon. Exp Mol Med 52(2):192–203
Kwon S et al (2019) Nanomedicines for reactive oxygen species mediated approach: an emerging paradigm for cancer treatment. Acc Chem Res 52(7):1771–1782
Li X et al (2018) Innovative strategies for hypoxic-tumor photodynamic therapy. Angew Chem Int Ed Engl 57(36):11522–11531
Agostinis P et al (2011) Photodynamic therapy of cancer: an update. CA Cancer J Clin 61(4):250–281
Hou Z et al (2015) UV-emitting upconversion-based TiO2 photosensitizing nanoplatform: near-infrared light mediated in vivo photodynamic therapy via mitochondria-involved apoptosis pathway. ACS Nano 9(3):2584–2599
Trachootham D, Alexandre J, Huang P (2009) Targeting cancer cells by ROS-mediated mechanisms: a radical therapeutic approach? Nat Rev Drug Discov 8(7):579–591
Vander Heiden MG, Cantley LC, Thompson CB (2009) Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324(5930):1029–1033
Finkel T (2011) Signal transduction by reactive oxygen species. J Cell Biol 194(1):7–15
Schumacker PT (2015) Reactive oxygen species in cancer: a dance with the devil. Cancer Cell 27(2):156–157
Reczek CR, Chandel NS (2017) The two faces of reactive oxygen species in cancer. Annu Rev Cancer Biol 1(1):79–98
Wang J, Yi J (2008) Cancer cell killing via ROS: to increase or decrease, that is the question. Cancer Biol Ther 7(12):1875–1884
Sztandera K, Gorzkiewicz M, Klajnert-Maculewicz B (2019) Gold nanoparticles in cancer treatment. Mol Pharm 16(1):1–23
Stapleton S, Jaffray D, Milosevic M (2017) Radiation effects on the tumor microenvironment: implications for nanomedicine delivery. Adv Drug Deliv Rev 109:119–130
Zhou Z et al (2016) Reactive oxygen species generating systems meeting challenges of photodynamic cancer therapy. Chem Soc Rev 45(23):6597–6626
Wang Z et al (2019) Janus nanobullets combine photodynamic therapy and magnetic hyperthermia to potentiate synergetic anti-metastatic immunotherapy. Adv Sci (Weinh) 6(22):1901690
Schieber M, Chandel NS (2014) ROS function in redox signaling and oxidative stress. Curr Biol 24(10):R453–R462
Dixon SJ, Stockwell BR (2014) The role of iron and reactive oxygen species in cell death. Nat Chem Biol 10(1):9–17
Lucky SS, Soo KC, Zhang Y (2015) Nanoparticles in photodynamic therapy. Chem Rev 115(4):1990–2042
Dougherty TJ et al (1998) Photodynamic therapy. J Natl Cancer Inst 90(12):889–905
Li X, Lee S, Yoon J (2018) Supramolecular photosensitizers rejuvenate photodynamic therapy. Chem Soc Rev 47(4):1174–1188
Wang J et al (2014) Carbon nanodots featuring efficient FRET for two-photon photodynamic cancer therapy with a low fs laser power density. Biomaterials 35(34):9372–9381
Saczko J et al (2015) Oxidative modification induced by photodynamic therapy with Photofrin(R)II and 2-methoxyestradiol in human ovarian clear carcinoma (OvBH-1) and human breast adenocarcinoma (MCF-7) cells. Biomed Pharmacother 71:30–36
Luo S et al (2011) A review of NIR dyes in cancer targeting and imaging. Biomaterials 32(29):7127–7138
Wang H et al (2015) Ultrathin black phosphorus nanosheets for efficient singlet oxygen generation. J Am Chem Soc 137(35):11376–11382
Zhang D et al (2018) Localized surface plasmon resonance enhanced singlet oxygen generation and light absorption based on black phosphorus@AuNPs nanosheet for tumor photodynamic/thermal therapy. Part Part Syst Character 35(4):1800010
Guo T et al (2018) Black phosphorus quantum dots with renal clearance property for efficient photodynamic therapy. Small 14(4):1702815
Chen W et al (2017) Black phosphorus nanosheet-based drug delivery system for synergistic photodynamic/photothermal/chemotherapy of cancer. Adv Mater 29(5):1603864
Ackerson CJ, Jadzinsky PD, Kornberg RD (2005) Thiolate ligands for synthesis of water-soluble gold clusters. J Am Chem Soc 127(18):6550–6551
Vankayala R et al (2014) First demonstration of gold nanorods-mediated photodynamic therapeutic destruction of tumors via near infra-red light activation. Small 10(8):1612–1622
Sun W et al (2020) Aggregation-induced emission gold clustoluminogens for enhanced low-dose x-ray-induced photodynamic therapy. Angew Chem Int Ed Engl 59(25):9914–9921
Han R et al (2020) Super-efficient in vivo two-photon photodynamic therapy with a gold nanocluster as a type I photosensitizer. ACS Nano 14(8):9532–9544
Hu X et al (2020) Biodegradation-mediated enzymatic activity-tunable molybdenum oxide nanourchins for tumor-specific cascade catalytic therapy. J Am Chem Soc 142(3):1636–1644
Sang Y et al (2020) Bioinspired construction of a nanozyme-based H2O2 homeostasis disruptor for intensive chemodynamic therapy. J Am Chem Soc 142(11):5177–5183
Ma B et al (2019) Self-assembled copper-amino acid nanoparticles for in situ glutathione “AND” H2O2 sequentially triggered chemodynamic therapy. J Am Chem Soc 141(2):849–857
Ranji-Burachaloo H et al (2018) Cancer treatment through nanoparticle-facilitated fenton reaction. ACS Nano 12(12):11819–11837
Zhang C et al (2016) Synthesis of iron nanometallic glasses and their application in cancer therapy by a localized fenton reaction. Angew Chem Int Ed Engl 55(6):2101–2106
Lin LS et al (2019) Synthesis of copper peroxide nanodots for H2O2 self-supplying chemodynamic therapy. J Am Chem Soc 141(25):9937–9945
Zhang L et al (2018) An adenosine triphosphate-responsive autocatalytic fenton nanoparticle for tumor ablation with self-supplied H2O2 and acceleration of Fe(III)/Fe(II) conversion. Nano Lett 18(12):7609–7618
Wang S et al (2019) Enhanced antitumor efficacy by a cascade of reactive oxygen species generation and drug release. Angew Chem Int Ed Engl 58(41):14758–14763
Liu G et al (2019) Mo2 C-derived polyoxometalate for NIR-II photoacoustic imaging-guided chemodynamic/photothermal synergistic therapy. Angew Chem Int Ed Engl 58(51):18641–18646
Bokare AD, Choi W (2014) Review of iron-free Fenton-like systems for activating H2O2 in advanced oxidation processes. J Hazard Mater 275:121–135
Gius D (2004) Redox-sensitive signaling factors and antioxidants: how tumor cells respond to ionizing radiation. J Nutr 134(11):3213s–3214s
Prousek J (2007) Fenton chemistry in biology and medicine. Pure Appl Chem 79(12):2325–2338
Storz P (2005) Reactive oxygen species in tumor progression. Front Biosci 10(2):1881–1896
Gupta SC et al (2012) Upsides and downsides of reactive oxygen species for cancer: the roles of reactive oxygen species in tumorigenesis, prevention, and therapy. Antioxid Redox Signal 16(11):1295–1322
Bystrom LM, Rivella S (2015) Cancer cells with irons in the fire. Free Radic Biol Med 79:337–342
Weinberg ED (1996) The role of iron in cancer. Eur J Cancer Prev 5(1):19–36
Kumar B et al (2008) Oxidative stress is inherent in prostate cancer cells and is required for aggressive phenotype. Cancer Res 68(6):1777–1785
Yu J et al (2019) Magnetic reactive oxygen species nanoreactor for switchable magnetic resonance imaging guided cancer therapy based on pH-sensitive Fe5C2@Fe3O4 nanoparticles. ACS Nano 13(9):10002–10014
Yang B et al (2020) A metal-organic framework (MOF) Fenton nanoagent-enabled nanocatalytic cancer therapy in synergy with autophagy inhibition. Adv Mater 32(12):e1907152
Fan H et al (2016) A smart photosensitizer-manganese dioxide nanosystem for enhanced photodynamic therapy by reducing glutathione levels in cancer cells. Angew Chem Int Ed Engl 55(18):5477–5482
Evens AM et al (2005) Motexafin gadolinium generates reactive oxygen species and induces apoptosis in sensitive and highly resistant multiple myeloma cells. Blood 105(3):1265–1273
Poyton MF et al (2016) Cu(2+) binds to phosphatidylethanolamine and increases oxidation in lipid membranes. J Am Chem Soc 138(5):1584–1590
Pelka J et al (2009) Cellular uptake of platinum nanoparticles in human colon carcinoma cells and their impact on cellular redox systems and dna integrity. Chem Res Toxicol 22(4):649–659
Pompella A et al (2003) The changing faces of glutathione, a cellular protagonist. Biochem Pharmacol 66(8):1499–1503
Chatterjee DK, Fong LS, Zhang Y (2008) Nanoparticles in photodynamic therapy: an emerging paradigm. Adv Drug Deliv Rev 60(15):1627–1637
Wang D et al (2014) Targeted iron-oxide nanoparticle for photodynamic therapy and imaging of head and neck cancer. ACS Nano 8(7):6620–6632
Lin LS et al (2018) Simultaneous Fenton-like ion delivery and glutathione depletion by MnO2-based nanoagent to enhance chemodynamic therapy. Angew Chem Int Ed Engl 57(18):4902–4906
Deng R et al (2011) Intracellular glutathione detection using MnO(2)-nanosheet-modified upconversion nanoparticles. J Am Chem Soc 133(50):20168–20171
Zhang K et al (2020) Enhanced cancer therapy by hypoxia-responsive copper metal-organic frameworks nanosystem. Biomaterials 258:120278
Krause M et al (2017) Cancer stem cells: radioresistance, prediction of radiotherapy outcome and specific targets for combined treatments. Adv Drug Deliv Rev 109:63–73
Goel S, Ni D, Cai W (2017) Harnessing the power of nanotechnology for enhanced radiation therapy. ACS Nano 11(6):5233–5237
Formenti SC, Demaria S (2009) Systemic effects of local radiotherapy. Lancet Oncol 10(7):718–726
Surace L et al (2015) Complement is a central mediator of radiotherapy-induced tumor-specific immunity and clinical response. Immunity 42(4):767–777
Ni K et al (2019) Ultrathin metal-organic layer-mediated radiotherapy-radiodynamic therapy enhances immunotherapy of metastatic cancers. Matter 1(5):1331–1353
Chen Q et al (2019) Nanoparticle-enhanced radiotherapy to trigger robust cancer immunotherapy. Adv Mater 31(10):e1802228
Gao M et al (2017) Erythrocyte-membrane-enveloped perfluorocarbon as nanoscale artificial red blood cells to relieve tumor hypoxia and enhance cancer radiotherapy. Adv Mater 29(35):1701429
Yong Y et al (2017) Polyoxometalate-based radiosensitization platform for treating hypoxic tumors by attenuating radioresistance and enhancing radiation response. ACS Nano 11(7):7164–7176
Yu Z et al (2015) A near-infrared triggered nanophotosensitizer inducing domino effect on mitochondrial reactive oxygen species burst for cancer therapy. ACS Nano 9(11):11064–11074
Fan WP et al (2015) Intelligent MnO2 nanosheets anchored with upconversion nanoprobes for concurrent pH-/H2O2-responsive UCL imaging and oxygen-elevated synergetic therapy. Adv Mater 27(28):4155–4161
Zhen X et al (2016) Intraparticle energy level alignment of semiconducting polymer nanoparticles to amplify chemiluminescence for ultrasensitive in vivo imaging of reactive oxygen species. ACS Nano 10(6):6400–6409
Chen Y et al (2019) Enhancement of mitochondrial ROS accumulation and radiotherapeutic efficacy using a Gd-doped titania nanosensitizer. Theranostics 9(1):167–178
Ma YC et al (2021) Nano-enabled coordination platform of bismuth nitrate and cisplatin prodrug potentiates cancer chemoradiotherapy via DNA damage enhancement. Biomater Sci 9(9):3401–3409
Hayyan M, Hashim MA, AlNashef IM (2016) Superoxide ion: generation and chemical implications. Chem Rev 116(5):3029–3085
Loving GS, Mukherjee S, Caravan P (2013) Redox-activated manganese-based MR contrast agent. J Am Chem Soc 135(12):4620–4623
Chen H, He W, Guo Z (2014) An H(2)O(2)-responsive nanocarrier for dual-release of platinum anticancer drugs and O(2): controlled release and enhanced cytotoxicity against cisplatin resistant cancer cells. Chem Commun (Camb) 50(68):9714–9717
Muhammad F et al (2011) pH-Triggered controlled drug release from mesoporous silica nanoparticles via intracelluar dissolution of ZnO nanolids. J Am Chem Soc 133(23):8778–8781
Thornton PD, Mart RJ, Ulijn RV (2007) Enzyme-responsive polymer hydrogel particles for controlled release. Adv Mater 19(9):1252–1256
D’Autreaux B, Toledano MB (2007) ROS as signalling molecules: mechanisms that generate specificity in ROS homeostasis. Nat Rev Mol Cell Biol 8(10):813–824
Winston GW, Giuli RTD (1991) Prooxidant and antioxidant mechanisms in aquatic organisms. Aquat Toxicol 19(2):137–161
Liou GY, Storz P (2010) Reactive oxygen species in cancer. Free Radic Res 44(5):479–496
Zan M et al (2014) Dual pH-triggered multistage drug delivery systems based on host–guest interaction-associated polymeric nanogels. Chem Commun (Camb) 50(58):7824–7827
We gratefully acknowledge the financial support by the Drug Innovation Major Projects (No. 2018ZX0921003-008-019).
This work was supported by the Drug Innovation Major Projects (No. 2018ZX09721003-008-019).
The authors declare that they have no competing interests.
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Xie, A., Li, H., Hao, Y. et al. Tuning the Toxicity of Reactive Oxygen Species into Advanced Tumor Therapy. Nanoscale Res Lett 16, 142 (2021). https://doi.org/10.1186/s11671-021-03599-8
- Reactive oxygen species
- Photodynamic therapy
- Chemodynamic therapy
- Tumor therapy