Advances in Clinical and Experimental Medicine

Title abbreviation: Adv Clin Exp Med
5-Year IF – 2.0, IF – 1.9, JCI (2024) – 0.43
Scopus CiteScore – 4.3
Q1 in SJR 2024, SJR score – 0.598, H-index: 49 (SJR)
IC – 171.00; MNiSW – 70 pts
Initial editorial assessment and first decision within 24 h

ISSN 1899–5276 (print), ISSN 2451-2680 (online)
Periodicity – monthly

Download original text (EN)

Advances in Clinical and Experimental Medicine

Ahead of print

doi: 10.17219/acem/191025

Publication type: review

Language: English

License: Creative Commons Attribution 3.0 Unported (CC BY 3.0)

Download citation:

  • BIBTEX (JabRef, Mendeley)
  • RIS (Papers, Reference Manager, RefWorks, Zotero)

Cite as:


Wolny D, Stojko M, Zajdel A. Novel strategies of glutathione depletion in photodynamic and chemodynamic therapy: A review [published online as ahead of print on September 20, 2024]. Adv Clin Exp Med. 2025. doi:10.17219/acem/191025

Novel strategies of glutathione depletion in photodynamic and chemodynamic therapy: A review

Daniel Wolny1,A,B,C,D,E,F, Mateusz Stojko2,B,D,F, Alicja Zajdel1,A,E,F

1 Department of Biopharmacy, Faculty of Pharmaceutical Sciences, Medical University of Silesia, Sosnowiec, Poland

2 Centre of Polymer and Carbon Materials, Polish Academy of Sciences, Zabrze, Poland

Graphical abstract


Graphical abstracts

Abstract

Cancer remains a health problem worldwide; therefore, developing new therapies to increase the effectiveness of anticancer treatments is necessary. Two such methods are photodynamic therapy (PDT) and chemodynamic therapy (CDT). The intensive growth and increased metabolism of tumors lead to elevated levels of reactive oxygen species (ROS) within cancer cells. These cells develop several antioxidant mechanisms to protect them from this oxidative stress. Antioxidants also make tumors more resistant to chemotherapy and radiation. Glutathione (GSH) is an important and the most abundant endogenous cellular antioxidant. Photodynamic therapy and CDT are new methods that are based on the production of ROS,- therefore increasing oxidative stress in cancer cells. A significant problem with these therapies is the increased GSH levels, which is an adaptation of cancer cells to augmented metabolic processes. This paper presents various GSH depletion strategies that are used to improve PDT and CDT. While the main goal of GSH depletion in both PDT and CDT is to prevent its interaction with the ROS generated by these therapies, it should be remembered that the reduction of its level itself may initiate pathways leading to cancer cell death.

Key words: photodynamic therapy, chemodynamic therapy, glutathione depletion

Introduction

The production of reactive oxygen species (ROS) is a natural consequence of oxygen metabolism and cellular biochemical reactions. As signaling molecules, ROS play an essential role in the activation of pathways that lead to cell proliferation and survival. However, in higher concentrations, they promote mutagenesis by damaging DNA, and in sufficiently high concentrations, they lead to oxidative stress, causing cell death. To prevent the adverse effects of high ROS levels, cells employ several antioxidant protective mechanisms to maintain cellular redox homeostasis and ensure normal functioning and survival.1

Contrary to normal cells, cancer cells are characterized by significantly increased levels of ROS owing to their unrestrained growth and increased metabolism.2 Moreover, higher levels of ROS increase the proliferation of cancer cells and tumor aggressiveness, promoting their ability to invade and metastasize.3 Increased ROS content forces cancer cells to intensify the antioxidant mechanisms that protect them from the negative effects of these oxidative stresses.2 It has also been postulated that cancer cells maintain the concentration of ROS at a level that facilitates their progression.4 The increased amount of antioxidants and constantly elevated levels of ROS found in cancer cells make them resistant to chemotherapeutic agents and radiation. It has also been shown that cancer cells are highly dependent on their antioxidant systems to maintain an appropriate redox level and are, therefore, sensitive to external factors disrupting these systems.1

Among the various endogenous cellular antioxidants, glutathione (GSH) is the most abundant. It is a major scavenger of ROS and plays an essential role in maintaining cell redox homeostasis. Although GSH plays an important role in the detoxification of carcinogens, its elevated concentration can be observed in many cancer types, which increases the resistance of such cells to the toxic effects of many chemotherapeutic agents and radiation.1

Due to the different amounts of ROS in cancer cells compared to normal cells, various tumor treatment strategies exacerbating oxidative stress have been developed.2 Since GSH is a common cellular antioxidant whose main function is to remove free radicals and maintain cellular redox balance, it appears to be the optimal target for such anticancer therapies. There are many studies showing that GSH depletion increases oxidative stress, which leads to cancer cell death. Moreover, it has been shown that the reduction of GSH content in cancer cells makes them more susceptible to factors that increase ROS.1

Objectives

Here, we describe GSH depletion strategies that could improve the effectiveness of 2 promising ROS-based treatments for cancer: photodynamic therapy (PDT) and chemodynamic (CDT) therapy.

Glutathione depletion strategies

Increased concentrations of GSH in tumor tissues compared to normal tissues have been observed in many neoplastic diseases.5 This increases the resistance of cancer cells to therapies based on potentiated oxidative stress.6 Depletion of GSH in cancer cells makes them more sensitive to therapeutic agents. Therefore, it should come as no surprise that various strategies are being developed to lower intracellular GSH levels to inhibit tumor growth and increase the effectiveness of therapy. These approaches include a reduction in the availability of substrates for GSH biosynthesis, inhibition of GSH synthesis, GSH conjugation, or increases in its oxidized form (GSSG), as well as promotion of GSH cellular efflux (Figure 1).7, 8, 9

Glutathione depletion in photodynamic therapy

Photodynamic therapy (Figure 2) is a new, developing anticancer therapy that is of great interest. The reasons for this are its undoubted advantages, such as low invasiveness, low toxicity, high effectiveness of therapy, and lack of drug resistance.10, 11, 12, 13, 14 Reactive oxygen species play a key role in PDT. They oxidize biological macromolecules, such as nucleic acids, proteins and lipids, altering cell signaling pathways and gene expression, as well as destroying membrane structures.15 This leads to apoptosis of cancer cells. Moreover, ROS within tumor tissues can also damage the microcirculation and cause immunogenic cell death.16, 17, 18 In this therapy, a photosensitizer (PS) is administered to the patient and activated with an appropriate wavelength of light. Photodynamic reactions can be classified into 2 types. In type I, light energy is transferred from excited molecules to biomolecules through a direct contact reaction. The radicalization mechanism involves the transfer of an electron or hydrogen, and the resulting radicals can initiate a radical chain reaction. This also produces superoxide radicals (O2•–) and hydroxyl radicals (•OH).19 Type II PDT is based on an indirect reaction, in which the excited PS reacts with molecular oxygen. As a result, singlet oxygen (1O2) is generated, which is extremely electrophilic, causing damage to biomolecules and, consequently, destroying neoplastic cells.20, 21 Most PDT in clinical applications are based on the second type of reaction.22

Due to some limitations, PDT is not currently used as a first-line therapy in cancer treatment.23, 24 To function effectively, it requires large amounts of oxygen in the tumor microenvironment (TME), which is unfortunately hypoxic.25 In addition, cells trigger several defense mechanisms in response to PDT, e.g., cancer cells increase the synthesis of various cytoprotective molecules. Redox-sensitive transcription factors are activated, which increases the amount of detoxification and antioxidant enzymes. Activation of anti-apoptotic pathways and overexpression of heat shock proteins prevent the formation of active apoptosomes.26

New strategies to increase the effectiveness of PDT are constantly being developed. These include an increase in ROS production by reducing hypoxia in the TME,17, 27 as well as reducing the efficiency of cancer cell antioxidant systems, with particular emphasis on GSH.19, 28

Hu et al. used docosahexaenoic acid (DHA) and 2,2-dimethoxy-2-phenylacetophenone (DMPA) placed in a ROS-sensitive dendrimer nanocarrier (RSV) to reduce intracellular GSH concentrations and increase the effectiveness of PDT.29 Zinc phthalocyanate (ZnPc) was used as the PS. Irradiated by 665 nm light in the presence of endogenous H2O2 or ROS resulting from PDT, RSV is decomposed, and DHA and DMPA are released. Under light irradiation, DMPA becomes the initiator of the thiol-ene click reaction, which consists of GSH conjugation to double bonds within the DHA molecule. This directly reduces the cellular concentration of GSH. Moreover, Hu et al. showed that their therapeutic system significantly decreased intracellular concentrations of ATP, which is a cofactor for γ-glutamylcysteine synthetase, resulting in inhibition of GSH synthesis.

Cao et al. synthesized nanoparticles from an amphiphilic branched copolymer (PEG) with pendant vinyl groups containing chlorine e6 (Ce6) as a PS.30 The vinyl groups form a hydrophobic core as the nanoparticle reacts with GSH in the thiol-ene click reaction, lowering its intracellular concentration while Ce6 is released.

Li et al. proposed the use of S-nitrosated human serum albumin (HSA-SNO) to lower GSH concentrations and increase the effectiveness of PDT therapy.31 HSA-SNO binds GSH molecules, releasing nitric oxide (NO), which additionally occupies oxygen binding sites within the mitochondria, thus reducing cellular respiration of cancer cells and indirectly increasing the oxygen concentration needed for PDT.14

The use of 5-aminolevulinic acid (ALA) as a clinically approved PS has been attempted. Although it does not have the ability to photosensitize itself, it undergoes metabolism inside the cell, resulting in the formation of protoporphyrin IX (PpIX), which already possesses such properties.32, 33 Compared to other PSs, ALA has low toxicity and is quickly removed from the body. However, at physiological pH, it is largely hydrophilic and, therefore, hardly penetrates biological barriers.34, 35 The use of ester derivatives alleviates this drawback, but due to the presence of a nucleophilic amino group, these compounds are still not very stable under physiological conditions. Li et al. synthesized a number of ALA methyl ester derivatives in which the substituents were linked to the amino group via 2-hydroxyethyl disulfide.36 After entering the cell, these derivatives react with GSH, which releases ALA and simultaneously lowers the intracellular GSH pool. Next, ALA was transformed into protoporphyrin IX.

An interesting solution was proposed by Meng et al., who created a metal-organic framework (MOF)-based nanocarrier using a disulfide-containing imidazole as an organic ligand and zinc (Zn2+) as a coordination metal.37 The nanocarrier was loaded with a PS (Ce6). To stabilize the MOF in an aqueous environment, its surface was covered with an amphiphilic polymer (pluronic F127). Glutathione depletion was accomplished through a disulfide-thiol exchange reaction and the decomposition of the MOF releases the PS. Meng et al. also demonstrated that the nanocarriers they used had a double therapeutic effect. The PS induces a typical PDT increase in ROS levels, leading to apoptosis. Glutathione depletion not only supports this process but also causes ferroptosis.38

Ferroptosis is a cell death pathway that includes an iron-dependent Fenton reaction and lipid peroxidation.39 This process is characterized by the accumulation of Lipids-OOH due to the disruption of their scavenging systems. The scavenging of toxic Lipids-OOH is carried out by their reduction to Lipids-OH by GSH peroxidase 4 (GPX4).40 Glutathione is the reducing co-substrate of GPX4; therefore, GSH depletion or GSH synthesis disorders can trigger ferroptosis.41 There are many studies that have observed ferroptosis initiated by GSH depletion in both PDT and CDT.37, 42, 43, 44, 45, 46

Curcumin, isolated from Curcuma longa, is a natural chemopreventive drug for cancer.47 Many studies have shown that this compound significantly decreases the level of hypoxia-inducible factor 1α (HIF-1α), which is overexpressed in several neoplastic diseases. Moreover, curcumin depletes GSH.48, 49 Zhang et al. used a curcumin derivative (Cur-S-OA) to create a nanoparticle (ZnPc@Cur-S-OA), which decomposes in cancer cells in a ROS-responsive manner with the release of the PS (zinc phthalocyanate, ZnPC) and free curcumin.50 The curcumin derivative serves 2 distinct purposes. First, it acts as a PS stabilizer. Second, following nanoparticle decomposition, it acts as a chemotherapeutic agent, thereby improving PDT efficiency.

Liu et al. designed an oxidative stress amplifier (OSA), that is activated in cancer cells by its interaction with H2O2.51 It is a micelle (DPL@CC) consisting of cinnamaldehyde (Cin), a GSH scavenger, and Ce6, a PS, coated with a ROS-reactive amphiphilic polymer (DPL). Cinnamal­dehyde conjugates with GSH and blocks its thiol group, which is required to react with ROS. After OSA application, the level of GSH decreased to 18.9% compared to control cells.

Cysteine is an essential substrate in GSH biosynthesis, and its deficiency significantly affects the formation rate and cellular concentration. Cystine, the oxidized form of cysteine, is present in the extracellular matrix (ECM) and is taken up by the cell through the Xc– system. It is an anti-port glutamate/cystine transporter found in the cell membrane.52 The light chain of the Xc– system (xCT) is overexpressed in many types of neoplastic diseases, which correlates with resistance to treatment and a poor prognosis in patients.53, 54, 55, 56 A reduction in extracellular cystine uptake directly reduces the cellular concentration of GSH; thus, inhibiting the Xc– system is another possible strategy for its depletion.57 One of the compounds with the ability to inhibit the Xc– system is erastin.39 Zhul et al. designed a nanodrug containing erastin and Ce6 as the PS.46 After entering cancer cells, erastin inhibited GSH biosynthesis, lowering the intracellular pool, enhancing Fe-induced lipid peroxidation, and inducing cell death via ferroptosis.39, 58, 59, 60, 61, 62

Wang et al. synthesized nanoparticles consisting of pyropheophorbide (PPa) as a PS and clopidogrel, which was responsible for increasing the effectiveness of PDT by GSH depletion.63 Clopidogrel is a classic antiplatelet drug that is metabolized by cytochrome P450 (CYP2C19) to form a thiol metabolite.64 This metabolite conjugates with GSH, lowering its intracellular pool and increasing the effectiveness of PDT. The disadvantage of this approach is that it is limited to cancer cells that overexpress CYP2C19.

Depletion of glutathione in chemodynamic therapy

Chemodynamic therapy (Figure 3) is highly selective towards cancer cells with minimal side effects.65 It is based on Fenton or Fenton-like reactions in which transition metal ions (e.g., Fe, Co, Ni, Cu, and Mn) react with hydrogen peroxide to form highly cytotoxic hydroxyl radicals (Fe2+ + H2O2 → Fe3+ + ●OH + OH–). This reaction is initiated in the TME, characterized by the overproduction of H2O2, low catalase activity and a weakly acidic pH.66, 67 Chemodynamic therapy is specific to cancer cells because the Fenton reaction is significantly limited in a weakly alkaline environment, and the limited amount of hydrogen peroxide is observed in normal cells.68 The Fenton reaction leads to oxidative stress, and the reactive hydroxyl radical reacts with proteins, lipids, and DNA, disrupting their function and leading to cancer cell death.65

Compared to PDT, CDT is more selective and is initiated by internal factors; therefore, it does not require external energy in the form of light and does not depend on local oxygen concentrations.69, 70 Nevertheless, some factors limit the effectiveness of CDT. The first is the limited amount of endogenous H2O2 in cancer cells and the low catalytic efficiency of chemodynamic agents.65 Another limitation is the reaction environment. Most chemodynamic agents, such as iron-based nanomaterials, transition metal ions, and metal-organic frameworks, catalyze Fenton and Fenton-like reactions better in a more acidic environment (pH 3.0–5.0) than in the TME (pH 6.0–7.0).65, 71 Finally, overexpression of GSH in the TME significantly reduces the production of hydroxyl radicals, reducing the effectiveness of CDT.65 Therefore, researchers have focused on designing new nanomaterials that increase the efficiency of CDT by modifying the TME, by lowering its pH, increasing H2O2 concentrations, and depleting GSH.

Lin et al. created nanoparticles consisting of mesoporous silica coated with manganese dioxide (MnO2).72 After internalization into cancer cells, the MnO2 envelope undergoes a redox reaction with GSH, resulting in the formation of the oxidized form of GSH (GSSG) and Mn2+ ions. Manganese ions in the presence of carbonate ions (HCO3–) react with H2O2, forming hydroxyl radicals through a Fenton-like reaction. Therefore, MnO2 plays a dual role. Its reaction with GSH lowers the intracellular pool, resulting in increased susceptibility of cancer cells to oxidative stress. The same reaction leads to the formation of Mn ions, which are responsible for ROS generation. The use of a mesoporous silica core, on the other hand, ensures the controlled release of the drug. It should be noted that a similar strategy has been used by many researchers.73

Compared with the classic Fenton reaction catalyzed by Fe2+ ions, a Fenton-like reaction is catalyzed by Cu+ ions and can be carried out with greater efficiency in a weakly acidic environment. However, because of the low redox potential of Cu+/Cu2+, Cu+ ions are easily oxidized to Cu2+.74, 75 Ma et al. proposed the use of copper-amino acid mercaptide nanoparticles (Cu-Cys NPs).76 After endocytosis into cancer cells, these nanoparticles oxidize GSH and the copper is reduced to Cu+ ions. These ions react with hydrogen peroxide to form hydroxyl radicals. The use of Cu2+ ions not only increases the efficiency of ROS production but is also an effective way to reduce the ratio of GSH to oxidized GSH (GSSG). The GSH depletion strategy using transition metal ions, which are reduced by GSH to substrates for the Fenton-like reaction, has been used in many studies.77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90

Chen et al. designed nanoparticles containing Fe3O4 and β-lapachone (Lapa).91 The first of these compounds is the source of Fe2+ ions, which participate in the Fenton reactions. Lapa undergoes a transition from quinone to hydroquinone in the futile cycle catalyzed by NADPH:quinone oxidoreductase-1 (NQO1). The overexpression of NQO1 in cancer cells, which occurs at a ratio of 2–100 times, results in greater selectivity for these cells when Lapa is used.92 The futile cycle of Lapa not only generates H2O2, increasing the efficiency of CDT, but also significantly reduces the cellular concentration of NADPH (60 mol/Lapa mol/5 min).93 Since NADPH is a coenzyme of GSH reductase, reduction in its amount interferes with the function of this GSSG-reducing enzyme. This leads to increased oxidative stress in cancer cells.

Limitations

Article selection bias is a possible limitation of this study. Due to the abundance of works on this review topic, despite every effort, some works that should have been cited may have been omitted. In addition, many of the papers used the same GSH depletion strategies, so the authors decided not to cite some of them.

Conclusions

Cancer remains a global health problem despite the constant development of new medicines. Numerous studies focused on developing new therapeutic strategies to increase the effectiveness of anticancer treatment. Methods, such as PDT or CDT, are characterized by an increased specificity and selectivity for cancer cells and reduced side effects compared to traditional chemo- and radiotherapy. Despite the undoubted advantages of these oxidative stress-increasing therapies, they face certain problems in clinical applications. One of the most important obstacles is the adaptation of cancer cells to an increased concentration of ROS by increasing the production of GSH. This requires the development of effective strategies to reduce the concentration of this thiol compound in cancer cells (Table 1). A simple and direct way to deplete GSH is to use compounds that react with GSH to form stable derivatives or transform it into an oxidized form (GSSG). This is also the most common strategy used by scientists to develop new PDTs and CDTs, as presented in this paper. Although the main goal of GSH depletion in both PDT and CDT is to prevent its interaction with ROS generated by these therapies, it should be remembered that reductions in GSH levels by itself may initiate pathways leading to cancer cell death.

Tables


Table 1. Glutathione depletion strategies during PDT and CDT

Type of therapy

Mode of action

Agent

References

PDT

conjugation with GSH

docohexaenoic acid

29

pendant vinyl groups

30

S-nitrosated human serum albumin

31

curcumin

50

cinnamaldehyde

51

thiol metabolite of clopidogrel

63

phenethyl isothiocyanate

94

mesoporous polydopamine

95

quinone methide

96

GSH oxidation

ALA derivative with disulfide bond

36, 97

disulfide-containing imidazole

37

hemin

98, 99

Cu2+

87, 88, 100, 101

Mn4+

89, 102, 103

Fe3+

84

NO

104

inhibition of GSH biosynthesis

erastin

46

buthionine sulfoximine

105

CDT

conjugation with GSH

2-nitroimidazole and 1H-imidazole-4-carbonitrile

106

GSH oxidation

Cu2+

76, 80, 81, 90, 107, 108

Mn4+

72, 86, 109

Fe3+

82, 110

NO

111

decrease of GSH reductase activity

β-lapachone

91

inhibition of GSH biosynthesis

triptolide

112
PDT – photodynamic therapy; CDT – chemodynamic therapy; GSH – glutathione; ALA – 5-aminolevulinic acid; Cu2+ – cupric ion; Mn4+ – tetravalent manganese ion; Fe3+ – ferric ion; NO – nitric oxide.

Figures


Fig. 1. Glutathione depletion strategies in cancer cells
Fig. 2. The principles of photodynamic therapy
Fig. 3. Chemodynamic therapy basis

References (112)

  1. Lv H, Zhen C, Liu J, Yang P, Hu L, Shang P. Unraveling the potential role of glutathione in multiple forms of cell death in cancer therapy. Oxid Med Cell Longev. 2019;2019:3150145. doi:10.1155/2019/3150145
  2. Gorrini C, Harris IS, Mak TW. Modulation of oxidative stress as an anticancer strategy. Nat Rev Drug Discov. 2013;12(12):931–947. doi:10.1038/nrd4002
  3. Kumar B, Koul S, Khandrika L, Meacham RB, Koul HK. Oxidative stress is inherent in prostate cancer cells and is required for aggressive phenotype. Cancer Res. 2008;68(6):1777–1785. doi:10.1158/0008-5472.CAN-07-5259
  4. Diehn M, Cho RW, Lobo NA, et al. Association of reactive oxygen species levels and radioresistance in cancer stem cells. Nature. 2009;458(7239):780–783. doi:10.1038/nature07733
  5. Gamcsik MP, Kasibhatla MS, Teeter SD, Colvin OM. Glutathione levels in human tumors. Biomarkers. 2012;17(8):671–691. doi:10.3109/1354750X.2012.715672
  6. Chen HHW, Kuo MT. Role of glutathione in the regulation of cisplatin resistance in cancer chemotherapy. Met Based Drugs. 2010;2010:430939. doi:10.1155/2010/430939
  7. Barattin R, Perrotton T, Trompier D, et al. Iodination of verapamil for a stronger induction of death, through GSH efflux, of cancer cells overexpressing MRP1. Bioorg Med Chem. 2010;18(17):6265–6274. doi:10.1016/j.bmc.2010.07.031
  8. Habermann KJ, Grünewald L, Van Wijk S, Fulda S. Targeting redox homeostasis in rhabdomyosarcoma cells: GSH-depleting agents enhance auranofin-induced cell death. Cell Death Dis. 2017;8(10):e3067. doi:10.1038/cddis.2017.412
  9. Lo M, Wang Y, Gout PW. The x cystine/glutamate antiporter: A potential target for therapy of cancer and other diseases. J Cell Physiol. 2008;215(3):593–602. doi:10.1002/jcp.21366
  10. Yun SH, Kwok SJJ. Light in diagnosis, therapy and surgery. Nat Biomed Eng. 2017;1(1):0008. doi:10.1038/s41551-016-0008
  11. Dolmans DEJGJ, Fukumura D, Jain RK. Photodynamic therapy for cancer. Nat Rev Cancer. 2003;3(5):380–387. doi:10.1038/nrc1071
  12. Lovell JF, Liu TWB, Chen J, Zheng G. Activatable photosensitizers for imaging and therapy. Chem Rev. 2010;110(5):2839–2857. doi:10.1021/cr900236h
  13. Cheng L, Wang C, Feng L, Yang K, Liu Z. Functional nanomaterials for phototherapies of cancer. Chem Rev. 2014;114(21):10869–10939. doi:10.1021/cr400532z
  14. Yu W, Liu T, Zhang M, et al. O2 economizer for inhibiting cell respiration to combat the hypoxia obstacle in tumor treatments. ACS Nano. 2019;13(2):1784–1794. doi:10.1021/acsnano.8b07852
  15. Dos Santos AF, De Almeida DRQ, Terra LF, Baptista MS, Labriola L. Photodynamic therapy in cancer treatment; An update review. J Cancer Metast Treat. 2019;5:25. doi:10.20517/2394-4722.2018.83
  16. Hou Z, Zhang Y, Deng K, et al. UV-emitting upconversion-based TiO2 photosensitizing nanoplatform: Near-infrared light mediated in vivo photodynamic therapy via mitochondria-involved apoptosis pathway. ACS Nano. 2015;9(3):2584–2599. doi:10.1021/nn506107c
  17. Li X, Kwon N, Guo T, Liu Z, Yoon J. Innovative strategies for hypoxic-tumor photodynamic therapy. Angew Chem Int Ed. 2018;57(36):11522–11531. doi:10.1002/anie.201805138
  18. Agostinis P, Berg K, Cengel KA, et al. Photodynamic therapy of cancer: An update. CA Cancer J Clin. 2011;61(4):250–281. doi:10.3322/caac.20114
  19. Ming L, Cheng K, Chen Y, Yang R, Chen D. Enhancement of tumor lethality of ROS in photodynamic therapy. Cancer Med. 2021;10(1):257–268. doi:10.1002/cam4.3592
  20. Liu Y, Liu Y, Bu W, et al. Hypoxia induced by upconversion-based photodynamic therapy: Towards highly effective synergistic bioreductive therapy in tumors. Angew Chem Int Ed. 2015;54(28):8105–8109. doi:10.1002/anie.201500478
  21. Van Straten D, Mashayekhi V, De Bruijn H, Oliveira S, Robinson D. Oncologic photodynamic therapy: Basic principles, current clinical status and future directions. Cancers (Basel). 2017;9(2):19. doi:10.3390/cancers9020019
  22. Zhou Z, Song J, Nie L, Chen X. Reactive oxygen species generating systems meeting challenges of photodynamic cancer therapy. Chem Soc Rev. 2016;45(23):6597–6626. doi:10.1039/C6CS00271D
  23. Moore CM, Pendse D, Emberton M. Photodynamic therapy for prostate cancer: A review of current status and future promise. Nat Rev Urol. 2009;6(1):18–30. doi:10.1038/ncpuro1274
  24. Wilson WR, Hay MP. Targeting hypoxia in cancer therapy. Nat Rev Cancer. 2011;11(6):393–410. doi:10.1038/nrc3064
  25. Feng L, Cheng L, Dong Z, et al. Theranostic liposomes with hypoxia-activated prodrug to effectively destruct hypoxic tumors post-photodynamic therapy. ACS Nano. 2017;11(1):927–937. doi:10.1021/acsnano.6b07525
  26. Nowis D, Makowski M, Stokłosa T, Legat M, Issat T, Gołab J. Direct tumor damage mechanisms of photodynamic therapy. Acta Biochim Pol. 2005;52(2):339–352. PMID:15990919.
  27. Larue, Myrzakhmetov, Ben-Mihoub, et al. Fighting hypoxia to improve PDT. Pharmaceuticals (Basel). 2019;12(4):163. doi:10.3390/ph12040163
  28. Kimani SG, Phillips JB, Bruce JI, MacRobert AJ, Golding JP. Antioxidant inhibitors potentiate the cytotoxicity of photodynamic therapy. Photochem Photobiol. 2012;88(1):175–187. doi:10.1111/j.1751-1097.2011.01022.x
  29. Hu J, Wang T, Zhou L, Wei S. A ROS responsive nanomedicine with enhanced photodynamic therapy via dual mechanisms: GSH depletion and biosynthesis inhibition. J Photochem Photobiol B. 2020;209:111955. doi:10.1016/j.jphotobiol.2020.111955
  30. Cao H, Zhong S, Wang Q, Chen C, Tian J, Zhang W. Enhanced photodynamic therapy based on an amphiphilic branched copolymer with pendant vinyl groups for simultaneous GSH depletion and Ce6 release. J Mater Chem B. 2020;8(3):478–483. doi:10.1039/C9TB02120E
  31. Li W, Yong J, Xu Y, et al. Glutathione depletion and dual-model oxygen balance disruption for photodynamic therapy enhancement. Colloids Surf B Biointerfaces. 2019;183:110453. doi:10.1016/j.colsurfb.2019.110453
  32. Xie J, Wang S, Li Z, et al. 5-aminolevulinic acid photodynamic therapy reduces HPV viral load via autophagy and apoptosis by modulating Ras/Raf/MEK/ERK and PI3K/AKT pathways in HeLa cells. J Photochem Photobiol B. 2019;194:46–55. doi:10.1016/j.jphotobiol.2019.03.012
  33. Tewari KM, Eggleston IM. Chemical approaches for the enhancement of 5-aminolevulinic acid-based photodynamic therapy and photodiagnosis. Photochem Photobiol Sci. 2018;17(11):1553–1572. doi:10.1039/c8pp00362a
  34. Kim, Johnson RP, Chung CW, Jeong YI, Kang DH, Suh H. Poly(L-histidine)-tagged 5-aminolevulinic acid prodrugs: New photosensitizing precursors of protoporphyrin IX for photodynamic colon cancer therapy. Int J Nanomed. 2012;7:2497–2512. doi:10.2147/IJN.S29582
  35. Fotinos N, Campo MA, Popowycz F, Gurny R, Lange N. 5-aminolevulinic acid derivatives in photomedicine: Characteristics, application and perspectives. Photochem Photobiol. 2006;82(4):994–1015. doi:10.1562/2006-02-03-IR-794
  36. Li K, Dong W, Miao Y, Liu Q, Qiu L, Lin J. Dual-targeted 5-aminolevulinic acid derivatives with glutathione depletion function for enhanced photodynamic therapy. J Photochem Photobiol B. 2021;215:112107. doi:10.1016/j.jphotobiol.2020.112107
  37. Meng X, Deng J, Liu F, et al. Triggered all-active metal organic framework: Ferroptosis machinery contributes to the apoptotic photodynamic antitumor therapy. Nano Lett. 2019;19(11):7866–7876. doi:10.1021/acs.nanolett.9b02904
  38. Forcina GC, Dixon SJ. GPX4 at the crossroads of lipid homeostasis and ferroptosis. Proteomics. 2019;19(18):1800311. doi:10.1002/pmic.201800311
  39. Dixon SJ, Lemberg KM, Lamprecht MR, et al. Ferroptosis: An iron-dependent form of nonapoptotic cell death. Cell. 2012;149(5):1060–1072. doi:10.1016/j.cell.2012.03.042
  40. Wang Y, Liu T, Li X, Sheng H, Ma X, Hao L. Ferroptosis-inducing nanomedicine for cancer therapy. Front Pharmacol. 2021;12:735965. doi:10.3389/fphar.2021.735965
  41. Niu B, Liao K, Zhou Y, et al. Application of glutathione depletion in cancer therapy: Enhanced ROS-based therapy, ferroptosis, and chemotherapy. Biomaterials. 2021;277:121110. doi:10.1016/j.biomaterials.2021.121110
  42. Tang H, Chen D, Li C, et al. Dual GSH-exhausting sorafenib loaded manganese-silica nanodrugs for inducing the ferroptosis of hepatocellular carcinoma cells. Int J Pharm. 2019;572:118782. doi:10.1016/j.ijpharm.2019.118782
  43. Wang S, Li F, Qiao R, et al. Arginine-rich manganese silicate nanobubbles as a ferroptosis-inducing agent for tumor-targeted theranostics. ACS Nano. 2018;12(12):12380–12392. doi:10.1021/acsnano.8b06399
  44. Tang H, Li C, Zhang Y, et al. Targeted manganese doped silica nano GSH-cleaner for treatment of liver cancer by destroying the intracellular redox homeostasis. Theranostics. 2020;10(21):9865–9887. doi:10.7150/thno.46771
  45. An P, Gao Z, Sun K, et al. Photothermal-enhanced inactivation of glutathione peroxidase for ferroptosis sensitized by an autophagy promotor. ACS Appl Mater Interfaces. 2019;11(46):42988–42997. doi:10.1021/acsami.9b16124
  46. Zhu T, Shi L, Yu C, et al. Ferroptosis promotes photodynamic therapy: Supramolecular photosensitizer-inducer nanodrug for enhanced cancer treatment. Theranostics. 2019;9(11):3293–3307. doi:10.7150/thno.32867
  47. Imran M, Ullah A, Saeed F, Nadeem M, Arshad MU, Suleria HAR. Cucurmin, anticancer, & antitumor perspectives: A comprehensive review. Crit Rev Food Sci Nutr. 2018;58(8):1271–1293. doi:10.1080/10408398.2016.1252711
  48. Liao W, Xiang W, Wang FF, Wang R, Ding Y. Curcumin inhibited growth of human melanoma A375 cells via inciting oxidative stress. Biomed Pharmacother. 2017;95:1177–1186. doi:10.1016/j.biopha.2017.09.026
  49. Bahrami A, Atkin SL, Majeed M, Sahebkar A. Effects of curcumin on hypoxia-inducible factor as a new therapeutic target. Pharmacol Res. 2018;137:159–169. doi:10.1016/j.phrs.2018.10.009
  50. Zhang Z, Wang R, Huang X, et al. Self-delivered and self-monitored chemo-photodynamic nanoparticles with light-triggered synergistic antitumor therapies by downregulation of HIF-1α and depletion of GSH. ACS Appl Mater Interfaces. 2020;12(5):5680–5694. doi:10.1021/acsami.9b23325
  51. Liu Y, Zhou Z, Liu Y, et al. H2 O2-activated oxidative stress amplifier capable of GSH scavenging for enhancing tumor photodynamic therapy. Biomater Sci. 2019;7(12):5359–5368. doi:10.1039/C9BM01354G
  52. Lewerenz J, Hewett SJ, Huang Y, et al. The cystine/glutamate antiporter system xc− in health and disease: From molecular mechanisms to novel therapeutic opportunities. Antioxid Redox Signal. 2013;18(5):522–555. doi:10.1089/ars.2011.4391
  53. Wada F, Koga H, Akiba J, et al. High expression of CD 44v9 and XCT in chemoresistant hepatocellular carcinoma: Potential targets by sulfasalazine. Cancer Sci. 2018;109(9):2801–2810. doi:10.1111/cas.13728
  54. Toyoda M, Kaira K, Ohshima Y, et al. Prognostic significance of amino-acid transporter expression (LAT1, ASCT2, and xCT) in surgically resected tongue cancer. Br J Cancer. 2014;110(10):2506–2513. doi:10.1038/bjc.2014.178
  55. Sugano K, Maeda K, Ohtani H, Nagahara H, Shibutani M, Hirakawa K. Expression of xCT as a predictor of disease recurrence in patients with colorectal cancer. Anticancer Res. 2015;35(2):677–682. PMID:25667445.
  56. Okuno S, Sato H, Kuriyama-Matsumura K, et al. Role of cystine transport in intracellular glutathione level and cisplatin resistance in human ovarian cancer cell lines. Br J Cancer. 2003;88(6):951–956. doi:10.1038/sj.bjc.6600786
  57. Savaskan NE, Hahnen E, Eyüpoglu IY. The x cystine/glutamate antiporter (xCT) as a potential target for therapy of cancer: Yet another cytotoxic anticancer approach? J Cell Physiol. 2009;220(2):531–532. doi:10.1002/jcp.21795
  58. Dixon SJ, Patel DN, Welsch M, et al. Pharmacological inhibition of cystine–glutamate exchange induces endoplasmic reticulum stress and ferroptosis. eLife. 2014;3:e02523. doi:10.7554/eLife.02523
  59. Xie Y, Hou W, Song X, et al. Ferroptosis: process and function. Cell Death Differ. 2016;23(3):369–379. doi:10.1038/cdd.2015.158
  60. Yang WS, Stockwell BR. Ferroptosis: Death by lipid peroxidation. Trends Cell Biol. 2016;26(3):165–176. doi:10.1016/j.tcb.2015.10.014
  61. Zheng DW, Lei Q, Zhu JY, et al. Switching apoptosis to ferroptosis: Metal–organic network for high-efficiency anticancer therapy. Nano Lett. 2017;17(1):284–291. doi:10.1021/acs.nanolett.6b04060
  62. Bogdan AR, Miyazawa M, Hashimoto K, Tsuji Y. Regulators of iron homeostasis: New players in metabolism, cell death, and disease. Trends Biochem Sci. 2016;41(3):274–286. doi:10.1016/j.tibs.2015.11.012
  63. Wang Q, Sun M, Li D, et al. Cytochrome P450 enzyme-mediated auto-enhanced photodynamic cancer therapy of co-nanoassembly between clopidogrel and photosensitizer. Theranostics. 2020;10(12):5550–5564. doi:10.7150/thno.42633
  64. Kazui M, Nishiya Y, Ishizuka T, et al. Identification of the human cytochrome P450 enzymes involved in the two oxidative steps in the bioactivation of clopidogrel to its pharmacologically active metabolite. Drug Metab Dispos. 2010;38(1):92–99. doi:10.1124/dmd.109.029132
  65. Wang X, Zhong X, Liu Z, Cheng L. Recent progress of chemodynamic therapy-induced combination cancer therapy. Nano Today. 2020;35:100946. doi:10.1016/j.nantod.2020.100946
  66. Gatenby RA, Gillies RJ. Why do cancers have high aerobic glycolysis? Nat Rev Cancer. 2004;4(11):891–899. doi:10.1038/nrc1478
  67. Nishikawa M, Tamada A, Kumai H, Yamashita F, Hashida M. Inhibition of experimental pulmonary metastasis by controlling biodistribution of catalase in mice. Int J Cancer. 2002;99(3):474–479. doi:10.1002/ijc.10387
  68. Szatrowski TP, Nathan CF. Production of large amounts of hydrogen peroxide by human tumor cells. Cancer Res. 1991;51(3):794–798. PMID:1846317.
  69. Tang Z, Liu Y, He M, Bu W. Chemodynamic therapy: Tumour microenvironment-mediated Fenton and Fenton-like reactions. Angew Chem Int Ed. 2019;58(4):946–956. doi:10.1002/anie.201805664
  70. Zhang C, Bu W, Ni D, et al. Synthesis of iron nanometallic glasses and their application in cancer therapy by a localized Fenton reaction. Angew Chem Int Ed. 2016;55(6):2101–2106. doi:10.1002/anie.201510031
  71. Fu S, Yang R, Zhang L, et al. Biomimetic CoO@AuPt nanozyme responsive to multiple tumor microenvironmental clues for augmenting chemodynamic therapy. Biomaterials. 2020;257:120279. doi:10.1016/j.biomaterials.2020.120279
  72. Lin L, Song J, Song L, et al. Simultaneous Fenton-like ion delivery and glutathione depletion by MnO2-based nanoagent to enhance chemodynamic therapy. Angew Chem Int Ed. 2018;57(18):4902–4906. doi:10.1002/anie.201712027
  73. Yang G, Ji J, Liu Z. Multifunctional MnO2 nanoparticles for tumor microenvironment modulation and cancer therapy. WIREs Nanomed Nanobiotechnol. 2021;13(6):e1720. doi:10.1002/wnan.1720
  74. Anandan S, Miyauchi M. Photocatalytic activity of Cu2+-grafted metal-doped ZnO photocatalysts under visible-light irradiation. Electrochemistry. 2011;79(10):842–844. doi:10.5796/electrochemistry.79.842
  75. Soltani T, Lee BK. Enhanced formation of sulfate radicals by metal-doped BiFeO3 under visible light for improving photo-Fenton catalytic degradation of 2-chlorophenol. Chem Eng J. 2017;313:1258–1268. doi:10.1016/j.cej.2016.11.016
  76. Ma B, Wang S, Liu F, et al. Self-assembled copper–amino acid nanoparticles for in situ glutathione and H2O 2 sequentially triggered hemodynamic therapy. J Am Chem Soc. 2019;141(2):849–857. doi:10.1021/jacs.8b08714
  77. Wang Z, Liu B, Sun Q, et al. Fusiform-like copper(II)-based metal–organic framework through relief hypoxia and GSH-depletion co-enhanced starvation and chemodynamic synergetic cancer therapy. ACS Appl Mater Interfaces. 2020;12(15):17254–17267. doi:10.1021/acsami.0c01539
  78. Cao S, Li X, Gao Y, et al. A simultaneously GSH-depleted bimetallic Cu(II) complex for enhanced chemodynamic cancer therapy. Dalton Trans. 2020;49(34):11851–11858. doi:10.1039/D0DT01742F
  79. Fu L, Wan Y, Qi C, et al. Nanocatalytic theranostics with glutathione depletion and enhanced reactive oxygen species generation for efficient cancer therapy. Adv Mater. 2021;33(7):2006892. doi:10.1002/adma.202006892
  80. Hu C, Cai L, Liu S, Liu Y, Zhou Y, Pang M. Copper-doped nanoscale covalent organic polymer for augmented photo/chemodynamic synergistic therapy and immunotherapy. Bioconjug Chem. 2020;31(6):1661–1670. doi:10.1021/acs.bioconjchem.0c00209
  81. Wu H, Chen F, Gu D, You C, Sun B. A pH-activated autocatalytic nanoreactor for self-boosting Fenton-like chemodynamic therapy. Nanoscale. 2020;12(33):17319–17331. doi:10.1039/D0NR03135F
  82. Wu H, Gu D, Xia S, Chen F, You C, Sun B. One-for-all intelligent core–shell nanoparticles for tumor-specific photothermal–chemodynamic synergistic therapy. Biomater Sci. 2021;9(3):1020–1033. doi:10.1039/D0BM01734E
  83. Tang W, Gao H, Ni D, et al. Bovine serum albumin-templated nanoplatform for magnetic resonance imaging-guided chemodynamic therapy. J Nanobiotechnol. 2019;17(1):68. doi:10.1186/s12951-019-0501-3
  84. Wang B, Dai Y, Kong Y, et al. Tumor microenvironment-responsive Fe(III)–porphyrin nanotheranostics for tumor imaging and targeted chemodynamic-photodynamic therapy. ACS Appl Mater Interfaces. 2020;12(48):53634–53645. doi:10.1021/acsami.0c14046
  85. Gu D, An P, He X, et al. A novel versatile yolk-shell nanosystem based on NIR-elevated drug release and GSH depletion-enhanced Fenton-like reaction for synergistic cancer therapy. Colloids Surf B Biointerfaces. 2020;189:110810. doi:10.1016/j.colsurfb.2020.110810
  86. He H, Yang Q, Li H, et al. Hollow mesoporous MnO2-carbon nanodot-based nanoplatform for GSH depletion enhanced chemodynamic therapy, chemotherapy, and normal/cancer cell differentiation. Microchim Acta. 2021;188(4):141. doi:10.1007/s00604-021-04801-5
  87. Chen M, Zhao S, Zhu J, et al. Open-source and reduced-expenditure nanosystem with ROS self-amplification and glutathione depletion for simultaneous augmented chemodynamic/photodynamic therapy. ACS Appl Mater Interfaces. 2022;14(18):20682–20692. doi:10.1021/acsami.2c01782
  88. Li Y, He G, Fu LH, et al. A microneedle patch with self-oxygenation and glutathione depletion for repeatable photodynamic therapy. ACS Nano. 2022;16(10):17298–17312. doi:10.1021/acsnano.2c08098
  89. Lu J, Mao Y, Feng S, et al. Biomimetic smart mesoporous carbon nanozyme as a dual-GSH depletion agent and O2 generator for enhanced photodynamic therapy. Acta Biomater. 2022;148:310–322. doi:10.1016/j.actbio.2022.06.001
  90. Shen WY, Jia CP, Liao LY, et al. Copper(II) complex enhanced chemodynamic therapy through GSH depletion and autophagy flow blockade. Dalton Trans. 2023;52(11):3287–3294. doi:10.1039/D2DT04108A
  91. Chen Q, Zhou J, Chen Z, Luo Q, Xu J, Song G. Tumor-specific expansion of oxidative stress by glutathione depletion and use of a Fenton nano­agent for enhanced chemodynamic therapy. ACS Appl Mater Interfaces. 2019;11(34):30551–30565. doi:10.1021/acsami.9b09323
  92. Ma X, Huang X, Moore Z, et al. Esterase-activatable β-lapachone prodrug micelles for NQO1-targeted lung cancer therapy. J Control Release. 2015;200:201–211. doi:10.1016/j.jconrel.2014.12.027
  93. Li LS, Bey EA, Dong Y, et al. Modulating endogenous NQO1 levels identifies key regulatory mechanisms of action of β-lapachone for pancreatic cancer therapy. Clin Cancer Res. 2011;17(2):275–285. doi:10.1158/1078-0432.CCR-10-1983
  94. Hu H, Chen J, Yang H, et al. Potentiating photodynamic therapy of ICG-loaded nanoparticles by depleting GSH with PEITC. Nanoscale. 2019;11(13):6384–6393. doi:10.1039/C9NR01306G
  95. Hu H, Liu X, Hong J, et al. Mesoporous polydopamine-based multifunctional nanoparticles for enhanced cancer phototherapy. J Colloid Interface Sci. 2022;612:246–260. doi:10.1016/j.jcis.2021.12.172
  96. Jung E, Kwon S, Song N, et al. Tumor-targeted redox-regulating and antiangiogenic phototherapeutics nanoassemblies for self-boosting phototherapy. Biomaterials. 2023;298:122127. doi:10.1016/j.biomaterials.2023.122127
  97. Li K, Dong W, Qiu L, et al. A new GSH-responsive prodrug of 5-aminolevulinic acid for photodiagnosis and photodynamic therapy of tumors. Eur J Med Chem. 2019;181:111582. doi:10.1016/j.ejmech.2019.111582
  98. Chen J, Chen F, Zhang L, et al. Self-assembling porphyrins as a single therapeutic agent for synergistic cancer therapy: A one stone three birds strategy. ACS Appl Mater Interfaces. 2021;13(24):27856–27867. doi:10.1021/acsami.1c04868
  99. Xiao X, Chen M, Zhang Y, et al. Hemin-incorporating DNA nanozyme enabling catalytic oxygenation and GSH depletion for enhanced photodynamic therapy and synergistic tumor ferroptosis. J Nanobiotechnol. 2022;20(1):410. doi:10.1186/s12951-022-01617-0
  100. Wang Y, Wu W, Liu J, et al. Cancer-cell-activated photodyna­mic therapy assisted by Cu(II)-based metal–organic framework. ACS Nano. 2019;13(6):6879–6890. doi:10.1021/acsnano.9b01665
  101. Xie Z, Liang S, Cai X, et al. O2-Cu/ZIF-8@Ce6/ZIF-8@F127 composite as a tumor microenvironment-responsive nanoplatform with enhanced photo-/chemodynamic antitumor efficacy. ACS Appl Mater Interfaces. 2019;11(35):31671–31680. doi:10.1021/acsami.9b10685
  102. Fan H, Yan G, Zhao Z, et al. A smart photosensitizer–manganese dioxide nanosystem for enhanced photodynamic therapy by reducing glutathione levels in cancer cells. Angew Chem Int Ed. 2016;55(18):5477–5482. doi:10.1002/anie.201510748
  103. Zhu J, Xiao T, Zhang J, et al. Surface-charge-switchable nanoclusters for magnetic resonance imaging-guided and glutathione depletion-enhanced photodynamic therapy. ACS Nano. 2020;14(9):11225–11237. doi:10.1021/acsnano.0c03080
  104. Deng Y, Jia F, Chen S, et al. Nitric oxide as an all-rounder for enhanced photodynamic therapy: Hypoxia relief, glutathione depletion and reactive nitrogen species generation. Biomaterials. 2018;187:55–65. doi:10.1016/j.biomaterials.2018.09.043
  105. Lee HM, Kim DH, Lee HL, Cha B, Kang DH, Jeong YI. Synergistic effect of buthionine sulfoximine on the chlorin e6-based photodynamic treatment of cancer cells. Arch Pharm Res. 2019;42(11):990–999. doi:10.1007/s12272-019-01179-0
  106. Li Y, Zhao P, Gong T, et al. Redox dyshomeostasis strategy for hypoxic tumor therapy based on DNAzyme-loaded electrophilic ZIFs. Angew Chem Int Ed. 2020;59(50):22537–22543. doi:10.1002/anie.202003653
  107. Zhang WX, Hao YN, Gao YR, Shu Y, Wang JH. Mutual benefit between Cu(II) and polydopamine for improving photothermal–chemodynamic therapy. ACS Appl Mater Interfaces. 2021;13(32):38127–38137. doi:10.1021/acsami.1c12199
  108. Jia S, Ke S, Tu L, et al. Glutathione/pH-responsive copper-based nanoplatform for amplified chemodynamic therapy through synergistic cycling regeneration of reactive oxygen species and dual glutathione depletion. J Colloid Interface Sci. 2023;652:329–340. doi:10.1016/j.jcis.2023.08.043
  109. Xu X, Zhang R, Yang X, et al. A honeycomb-like bismuth/manganese oxide nanoparticle with mutual reinforcement of internal and external response for triple-negative breast cancer targeted therapy. Adv Healthc Mater. 2021;10(18):2100518. doi:10.1002/adhm.202100518
  110. Yang X, Wang L, Guo S, et al. Self-cycling free radical generator from LDH-based nanohybrids for ferroptosis-enhanced chemodynamic therapy. Adv Healthc Mater. 2021;10(18):2100539. doi:10.1002/adhm.202100539
  111. Yu W, Jia F, Fu J, et al. Enhanced transcutaneous chemodynamic therapy for melanoma treatment through cascaded Fenton-like reactions and nitric oxide delivery. ACS Nano. 2023;17(16):15713–15723. doi:10.1021/acsnano.3c02964
  112. Huang Y, Wu S, Zhang L, Deng Q, Ren J, Qu X. A metabolic multistage glutathione depletion used for tumor-specific chemodynamic therapy. ACS Nano. 2022;16(3):4228–4238. doi:10.1021/acsnano.1c10231
© Wroclaw Medical University