Selectivity in Photodynamic Action: Higher Activity of Mitochondria Targeting Photosensitizers in Cancer Cells

Uçar, Esma; Seven, Özlem; Lee, Da-Young; Kim, Gyoungmi; Yoon, Juyoung; Akkaya, Engin U.

doi:10.1002/cptc.201800231

Cited by 22 publications

(22 citation statements)

References 43 publications

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“…Therefore, it seems clear that the subcellular location of the PS has a major impact on the effectiveness of PDT. As a result, several studies investigated the effects of utilizing organelle targeted PSs, which localize to nucleus, mitochondria or lysosomes ( Karaman et al, 2019 ; Ucar et al, 2019 ). Indeed, such approaches might improve the outcome of PDT ( Wan et al, 2020 ; Qiao et al, 2021 ).…”

Section: Novel Approaches To Improve Outcomementioning

confidence: 99%

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: Novel Approaches To Improve Outcomementioning

confidence: 99%

Photodynamic Therapy—Current Limitations and Novel Approaches

2021

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“…Mitochondria participate in cell cycle control, growth, differentiation, and play an essential role in Ca 2+ homeostasis (Area-Gomez et al, 2019;Madreiter-Sokolowski et al, 2019;Woods et al, 2019). For mitochondria, the consequence of placing the oxidative metabolism is the primary generation of superoxide ion that leads to the formation of secondary pro-oxidant species such as hydrogen peroxide, peroxynitrite, hydroxyl radicals, carbon-centered radicals, triplet carbonyls, and singlet oxygen (Misztal et al, 2013;Miyamoto et al, 2014;Prasad et al, 2018;Radi, 2018;Ucar et al, 2019). Mitochondrial oxidative and nitrosative stress is implicated in degenerative and cardiovascular diseases (Liguori et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Cardiolipin Structure and Oxidation Are Affected by Ca2+ at the Interface of Lipid Bilayers

et al. 2020

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Ca 2+-overload contributes to the oxidation of mitochondrial membrane lipids and associated events such as the permeability transition pore (MPTP) opening. Numerous experimental studies about the Ca 2+ /cardiolipin (CL) interaction are reported in the literature, but there are few studies in conjunction with theoretical approaches based on ab initio calculations. In the present study, the lipid fraction of the inner mitochondrial membrane was modeled as POPC/CL large unilamellar vesicles (LUVs). POPC/CL and, comparatively, POPC, and CL LUVs were challenged by singlet molecular oxygen using the anionic porphyrin TPPS4 as a photosensitizer and by free radicals produced by Fe 2+-citrate. Calcium ion favored both types of lipid oxidation in a lipid composition-dependent manner. In membranes containing predominantly or exclusively POPC, Ca 2+ increased the oxidation at later reaction times while the oxidation of CL membranes was exacerbated at the early times of reaction. Considering that Ca 2+ interaction affects the lipid structure and packing, density functional theory (DFT) calculations were applied to the Ca 2+ association with totally and partially protonated and deprotonated CL, in the presence of water. The interaction of totally and partially protonated CL head groups with Ca 2+ decreased the intramolecular P-P distance and increased the hydrophobic volume of the acyl chains. Consistently with the theoretically predicted effect of Ca 2+ on CL, in the absence of pro-oxidants, giant unilamellar vesicles (GUVs) challenged by Ca 2+ formed buds and many internal vesicles. Therefore, Ca 2+ induces changes in CL packing and increases the susceptibility of CL to the oxidation promoted by free radicals and excited species.

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“…Clearly, low energy light (600-900 nm) has better tissue penetration due to the lack of auto-fluorescence and minimum interference from bio-molecules. [20][21] BODIPY dyes, after the pioneering study of Nagano in 2005, [22] have emerged as an attractive PS core. [14][15] Additionally, MT are known to have a negative transmembrane potential and the membrane potential in cancer cells was shown to be higher compared to healthy cells, suggesting privileged accumulation and retention of cationic agents in cancerous cells.…”

Section: Introductionmentioning

confidence: 99%

“…[16][17][18][19] Accordingly, MT targeted PDT agents can exhibit improved cytotoxicity even under hypoxic conditions as a result of high mitochondrial oxygen content and MT-induced apoptosis, while satisfying the cancer cell selectivity as previously reported. [28] There are also several reports on MT targeted BODIPY-based PDT drugs; [21,[29][30] however, a MT targeted BODIPY-based PS which can function under hypoxic conditions have not been reported yet. [23][24] Plenty of promising BODIPY-based PSs with different characteristics have been introduced in the past years including several agents that can selectively kill the cancer cells.…”

Section: Introductionmentioning

confidence: 99%

Mitochondria‐Targeting Selenophene‐Modified BODIPY‐Based Photosensitizers for the Treatment of Hypoxic Cancer Cells

et al. 2019

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Two red-absorbing, water-soluble and mitochondria (MT)targeting selenophene-substituted BODIPY-based photosensitizers (PSs) were realized (BODÀ Se, BODÀ SeÀ I), and their potential as photodynamic therapy (PDT) agents were evaluated. BODÀ SeÀ I showed higher 1 O 2 generation yield thanks to the enhanced heavy-atom effect, and this derivative was further tested in detail in cell culture studies under both normoxic and hypoxic conditions. BODÀ SeÀ I not only effectively functioned under hypoxic conditions, but also showed highly selective photocytotoxicity towards cancer cells. The selectivity is believed to arise from differences in mitochondrial membrane potentials of healthy and cancerous cells. To the best of our knowledge, this marks the first example of a MT-targeted BODIPY PS that functions under hypoxic conditions. Remarkably, thanks to the design strategy, all these properties where realized by a compound that was synthesized in only five steps with 32 % overall yield. Hence, this material holds great promise for the realization of next-generation PDT drugs for the treatment of hypoxic solid tumors.

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Selectivity in Photodynamic Action: Higher Activity of Mitochondria Targeting Photosensitizers in Cancer Cells

Cited by 22 publications

References 43 publications

Photodynamic Therapy—Current Limitations and Novel Approaches

Photodynamic Therapy—Current Limitations and Novel Approaches

Cardiolipin Structure and Oxidation Are Affected by Ca2+ at the Interface of Lipid Bilayers

Mitochondria‐Targeting Selenophene‐Modified BODIPY‐Based Photosensitizers for the Treatment of Hypoxic Cancer Cells

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