Proof-of-principle for two-stage photodynamic therapy: hypoxia triggered release of singlet oxygen

Ayan, Seylan; Günaydın, Gürcan; Yesilgul-Mehmetcik, Nisa; Gedik, M. Emre; Seven, Özlem; Akkaya, Engin U.

doi:10.1039/d0cc06031c

Cited by 40 publications

(26 citation statements)

References 23 publications

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“…Two stage PDT can overcome the issues of light attenuation and oxygen deficiency in tumors. Reproduced from (Ayan et al, 2020) (published by The Royal Society of Chemistry) with permission from the Royal Society of Chemistry. FIGURE 8 | Fractional PDT.…”

Section: Low Ph and High Intracellular Glutathione (Gsh) Concentrationmentioning

confidence: 99%

“…It remains in an “OFF” state (inactivated PS), unless activated by chemical/biochemical parameters into the “ON” state (activated PS) in the tumor region. Examples of such parameters are overexpressed enzymes/proteins ( Yuan et al, 2014 ; Digby et al, 2020 ) and higher intracellular glutathione concentration in cancer cells ( Cakmak et al, 2011 ; Turan et al, 2014 ; Erbas-Cakmak et al, 2015 ; Kolemen et al, 2015 ); hydrogen peroxide ( Wang Y. et al, 2021 ); low pH of the environment ( Tian et al, 2015 ); hypoxia ( Ayan et al, 2020 ) and cathepsin B ( Kim et al, 2014 ). The working principle of this switch generally involves cleavage of an intramolecular linker, which is connected to the PS as a quenching moiety.…”

Section: Novel Approaches To Improve Outcomementioning

confidence: 99%

“…Once triggered by hypoxia, the endoperoxide product was bioreductively changed (Stage II) into a more labile version of itself. Thus, it will specifically generate singlet oxygen, causing “apoptotic response” without depending on, or depleting already low tissue oxygen levels in tumors ( Figure 7 ) ( Ayan et al, 2020 ).…”

Section: Novel Approaches To Improve Outcomementioning

confidence: 99%

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Photodynamic Therapy—Current Limitations and Novel Approaches

2021

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Photodynamic therapy (PDT) mostly relies on the generation of singlet oxygen, via the excitation of a photosensitizer, so that target tumor cells can be destroyed. PDT can be applied in the settings of several malignant diseases. In fact, the earliest preclinical applications date back to 1900’s. Dougherty reported the treatment of skin tumors by PDT in 1978. Several further studies around 1980 demonstrated the effectiveness of PDT. Thus, the technique has attracted the attention of numerous researchers since then. Hematoporphyrin derivative received the FDA approval as a clinical application of PDT in 1995. We have indeed witnessed a considerable progress in the field over the last century. Given the fact that PDT has a favorable adverse event profile and can enhance anti-tumor immune responses as well as demonstrating minimally invasive characteristics, it is disappointing that PDT is not broadly utilized in the clinical setting for the treatment of malignant and/or non-malignant diseases. Several issues still hinder the development of PDT, such as those related with light, tissue oxygenation and inherent properties of the photosensitizers. Various photosensitizers have been designed/synthesized in order to overcome the limitations. In this Review, we provide a general overview of the mechanisms of action in terms of PDT in cancer, including the effects on immune system and vasculature as well as mechanisms related with tumor cell destruction. We will also briefly mention the application of PDT for non-malignant diseases. The current limitations of PDT utilization in cancer will be reviewed, since identifying problems associated with design/synthesis of photosensitizers as well as application of light and tissue oxygenation might pave the way for more effective PDT approaches. Furthermore, novel promising approaches to improve outcome in PDT such as selectivity, bioengineering, subcellular/organelle targeting, etc. will also be discussed in detail, since the potential of pioneering and exceptional approaches that aim to overcome the limitations and reveal the full potential of PDT in terms of clinical translation are undoubtedly exciting. A better understanding of novel concepts in the field (e.g. enhanced, two-stage, fractional PDT) will most likely prove to be very useful for pursuing and improving effective PDT strategies.

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Section: Low Ph and High Intracellular Glutathione (Gsh) Concentrationmentioning

confidence: 99%

Section: Novel Approaches To Improve Outcomementioning

confidence: 99%

Section: Novel Approaches To Improve Outcomementioning

confidence: 99%

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Photodynamic Therapy—Current Limitations and Novel Approaches

2021

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“…Problems such as lack of selectivity, poor water-solubility, possible toxic effects on healthy tissues, skin photosensitivity that is associated with certain PSs may prevent the clinical applications of various PDT approaches. Many research groups have undertaken the task to overcome such issues and several promising targeted approaches have been reported over the last years ( Turan et al, 2016 ; Karaman et al, 2019 ; Ayan et al, 2020 ). Novel innovative strategies aim to increase the delivery of PSs to tumor tissues, to augment specificity and to increase efficiency ( Bugaj, 2011 ).…”

Section: Clinical Applications Of Photodynamic Therapy In Cancermentioning

confidence: 99%

“…Therefore, cancer cells require a robust antioxidant system in order to be able to survive. It was reported that the cytotoxic effects of PDT are enhanced when antioxidant enzymes or glutathione synthesis mechanisms are targeted during PDT ( Ayan et al, 2020 ). It was demonstrated that l -buthionine sulfoximine, which is a glutathione synthesis inhibitor, boosts PDT effects.…”

Section: Clinical Applications Of Photodynamic Therapy In Cancermentioning

confidence: 99%

Photodynamic Therapy for the Treatment and Diagnosis of Cancer–A Review of the Current Clinical Status

2021

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Photodynamic therapy (PDT) has been used as an anti-tumor treatment method for a long time and photosensitizers (PS) can be used in various types of tumors. Originally, light is an effective tool that has been used in the treatment of diseases for ages. The effects of combination of specific dyes with light illumination was demonstrated at the beginning of 20th century and novel PDT approaches have been developed ever since. Main strategies of current studies are to reduce off-target effects and improve pharmacokinetic properties. Given the high interest and vast literature about the topic, approval of PDT as the first drug/device combination by the FDA should come as no surprise. PDT consists of two stages of treatment, combining light energy with a PS in order to destruct tumor cells after activation by light. In general, PDT has fewer side effects and toxicity than chemotherapy and/or radiotherapy. In addition to the purpose of treatment, several types of PSs can be used for diagnostic purposes for tumors. Such approaches are called photodynamic diagnosis (PDD). In this Review, we provide a general overview of the clinical applications of PDT in cancer, including the diagnostic and therapeutic approaches. Assessment of PDT therapeutic efficacy in the clinic will be discussed, since identifying predictors to determine the response to treatment is crucial. In addition, examples of PDT in various types of tumors will be discussed. Furthermore, combination of PDT with other therapy modalities such as chemotherapy, radiotherapy, surgery and immunotherapy will be emphasized, since such approaches seem to be promising in terms of enhancing effectiveness against tumor. The combination of PDT with other treatments may yield better results than by single treatments. Moreover, the utilization of lower doses in a combination therapy setting may cause less side effects and better results than single therapy. A better understanding of the effectiveness of PDT in a combination setting in the clinic as well as the optimization of such complex multimodal treatments may expand the clinical applications of PDT.

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Targeted Singlet Oxygen Delivery: A Bioorthogonal Metabolic Shunt Linking Hypoxia to Fast Singlet Oxygen Release

Wang

et al. 2022

Angewandte Chemie

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Singlet oxygen can be generated by thermal cycloreversion of aromatic endoperoxides. However, for any practical potential of chemically generated singlet oxygen within a therapeutic context, the time and place of the release of this cytotoxic species must be tightly regulated. We now show that using a bimodular design with a hypoxia responsive unit and fluoride‐triggered endoperoxide unit, a bioorthogonal metabolic shunt can be established, where an enzymatically generated submicromolar fluoride signal plays a crucial role. Thus, cellular nitroreductase is repurposed in a bioorthogonal enzymatic activity, where it releases fluoride ions upon the reduction of a targeted compound. The fluoride ions released in the initial reaction remove the silyl stopper, yielding a highly accelerated release of singlet oxygen. The result is a remarkable difference in cytotoxicity between hypoxic and normoxic conditions as evidenced by microscopy, viability assays and the use of control compounds.

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Proof-of-principle for two-stage photodynamic therapy: hypoxia triggered release of singlet oxygen

Abstract: Singlet oxygen, which is stored in the form of an endoperoxide, released under hypoxic conditions typically prevalent in most tumors.

Cited by 40 publications

References 23 publications

Photodynamic Therapy—Current Limitations and Novel Approaches

Photodynamic Therapy—Current Limitations and Novel Approaches

Photodynamic Therapy for the Treatment and Diagnosis of Cancer–A Review of the Current Clinical Status

Targeted Singlet Oxygen Delivery: A Bioorthogonal Metabolic Shunt Linking Hypoxia to Fast Singlet Oxygen Release

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