Polymeric Iron Chelators Enhancing Pro-Oxidant Antitumor Efficacy of Vitamin C by Inhibiting the Extracellular Fenton Reaction

Guo, Hongbo; Nomoto, Takahiro; Muttaqien, Sjaikhurrizal El; Sun, Xiaohang; Komoto, Kana; Matsui, Makoto; Miura, Yutaka; Nishiyama, Nobuhiro

doi:10.1021/acs.molpharmaceut.1c00673

Cited by 5 publications

(4 citation statements)

References 33 publications

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“… 14 In addition, we have recently reported that Polymer‐DFO has potential to modulate tumor microenvironment by chelating intratumoral iron and facilitate pro‐oxidant activity of vitamin C in a target tumor by inhibiting an unfavorable iron‐mediated redox reaction, thereby improving the anticancer effect of high‐dose vitamin C in in vivo. 23 We therefore expected that Polymer‐DFO might improve accumulation of 5‐ALA‐derived PpIX, and it indeed enhanced the therapeutic potency in CT26 tumor models (Figure 5 ).…”

Section: Discussionmentioning

confidence: 91%

Polymeric iron chelators for enhancing 5‐aminolevulinic acid‐induced photodynamic therapy

et al. 2022

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5-Aminolevulinic acid (5-ALA) is an amino acid that can be metabolized into a photosensitizer, protoporphyrin IX (PpIX) selectively in a tumor cell, permitting minimally invasive photodynamic diagnosis/therapy. However, some malignant tumor cells have excess intracellular labile iron and facilitate the conversion of PpIX into heme, which compromises the therapeutic potency of 5-ALA. Here, we examined the potential of chelation of such unfavorable intratumoral labile iron in photodynamic therapy (PDT) with 5-ALA hydrochloride, using polymeric iron chelators that we recently developed. The polymeric iron chelator efficiently inactivated the intracellular labile iron in cultured cancer cells and importantly enhanced the accumulation of PpIX, thereby improving the cytotoxicity upon photoirradiation. Even in in vivo study with subcutaneous tumor models, the polymeric iron chelator augmented the intratumoral accumulation of PpIX and the PDT effect. This study suggests that our polymeric iron chelator could be a tool for boosting the effect of 5-ALA-induced PDT by modulating tumor microenvironment.

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Section: Discussionmentioning

confidence: 91%

Polymeric iron chelators for enhancing 5‐aminolevulinic acid‐induced photodynamic therapy

et al. 2022

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“…The generation of excessive ROS due to the reaction between metal ions and H 2 O 2 is responsible for the rapid degradation of proteins. Fenton reaction, which leads to the formation of hydroxyl free radicals, has been studied in many chemical and biochemical systems. ,, The free radicals perturb the protein structure by oxidatively damaging the amino acids, eventually leading to the formation of aggregates and breakage of polypeptide chains. ,, There are various published studies where the oxidation of amino acids and oxidation mediated damage of proteins in terms of aggregation and fragmentation have been explored. ,,− The detailed mechanism of Fenton-reaction-mediated aggregation is shown in Figure . Furthermore, interactions of metal ions to the protein backbone and amino acids, and the presence of nonprotein components in protein aggregates have also been published in various studies which explored metal-catalyzed degradation of proteins. ,, Hence, non-protein components in aggregates of mAb in the current study can be characterized further in future studies.…”

Section: Discussionmentioning

confidence: 99%

“…12,18,22 The free radicals perturb the protein structure by oxidatively damaging the amino acids, eventually leading to the formation of aggregates and breakage of polypeptide chains. 35,49,52 There are various published studies where the oxidation of amino acids and oxidation mediated damage of proteins in terms of aggregation and fragmentation have been explored. 10,17,42−45 The detailed mechanism of Fenton-reaction-mediated aggregation is shown in Figure 10.…”

Section: Discussionmentioning

confidence: 99%

Combined Presence of Ferrous Ions and Hydrogen Peroxide in Normal Saline and In Vitro Models Induces Enhanced Aggregation of Therapeutic IgG due to Hydroxyl Radicals

Sreenivasan

Rathore

2023

Mol. Pharmaceutics

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Therapeutic monoclonal antibodies (mAb) are known to form aggregates and fragments upon exposure to hydrogen peroxide (H 2 O 2 ) and ferrous ions (Fe 2+ ). H 2 O 2 and Fe 2+ react to form hydroxyl radicals that are detrimental to protein structures. In this study, aggregation of mAb in the combined presence of Fe 2+ and H 2 O 2 was investigated in saline and physiologically relevant in vitro models. In the first case study, forced degradation of mAb in saline (a fluid used for administration of mAb) was carried out at 55 °C in the combined presence of 0.2 mM Fe 2+ and 0.1% H 2 O 2 . The control and stressed samples were analyzed using an array of techniques including visual observation, size-exclusion chromatography (SEC), dynamic light scattering (DLS), microscopy, UV−vis, fluorescence, Fourier transform infrared spectroscopy, and cell-based toxicity assays. At the end of 1 h, samples having the combined presence of both Fe 2+ and H 2 O 2 exhibited more than 20% HMW (high molecular weight species), whereas samples having only Fe 2+ , H 2 O 2 , or neither resulted in less than 3% HMW. Aggregate-rich samples also exhibited altered protein structures and hydrophobicity. Aggregation increased upon increasing the time, temperature, and concentration of Fe 2+ and H 2 O 2 . Samples having both Fe 2+ and H 2 O 2 also showed higher cytotoxicity in red blood cells. Samples of mAb with chlorides of copper and cobalt with H 2 O 2 also resulted in multifold degradation. The first case study showed enhanced aggregation of mAb in the combined presence of Fe 2+ and H 2 O 2 in saline. In the second case study, aggregation of mAb was investigated in artificially prepared extracellular saline and in vitro models such as macromolecule free fraction of serum and serum. In the presence of both Fe 2+ and H 2 O 2 , %HMW was higher in extracellular saline compared to macromolecule free fraction of serum. Further, in vitro models having the combined presence of Fe 2+ and H 2 O 2 resulted in enhanced aggregation of mAb compared to models that had neither.

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“…This is because the high plasma concentration of vitamin C (up to 6 mM) can be achieved only via intravenous administration. Moreover, a polymeric iron chelator is designed that prevents the pro-oxidant property of vitamin C outside of the cell and ensures ROS generation inside of the cell . We expect that the nano-vitamin C-based approach can be extended in utilizing the full potential of the pro-oxidant property of vitamin C.…”

Section: Discussionmentioning

confidence: 99%

Enhanced Therapeutic Applications of Vitamin C via Nanotechnology-Based Pro-Oxidant Properties: A Review

Pal

Jana

2022

ACS Appl. Nano Mater.

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Vitamin C has a controversial history in terms of its antioxidant as well as pro-oxidant properties. While the antioxidant property of vitamin C is an established fact, the pro-oxidant property is less known. This is particularly because the pro-oxidant property of vitamin C occurs only under selected conditions that include high concentration and/or the presence of a catalytic metal. Recent works show that the nanoformulation of vitamin C or the coupling with a nanoparticle can significantly enhance the pro-oxidant property of vitamin C. This Review has focused on the current status of the utilization of the pro-oxidant property of vitamin C in various therapeutic applications. In particular, the design of the nanoparticle form of vitamin C and the other nanotechnology approach to enhance the pro-oxidant property of vitamin C have been reviewed. We discuss the chemical origin of the antioxidant or the pro-oxidant property of vitamin C under different conditions and highlight the advantages of the nanoparticle form of vitamin C (or nano-vitamin C) in enhancing the performance. It has been shown that nanotechnology approaches offer an enhanced cell delivery of vitamin C with enhanced intracellular Fenton reaction-based oxidative stress and Ferroptosis therapy. As a result, the pro-oxidant property of vitamin C can now be utilized at a physiologically relevant vitamin C concentration that was not possible earlier. We expect that nanotechnology approaches of enhancing the pro-oxidant property of vitamin C would emerge as a powerful therapeutic approach.

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Polymeric Iron Chelators Enhancing Pro-Oxidant Antitumor Efficacy of Vitamin C by Inhibiting the Extracellular Fenton Reaction

Cited by 5 publications

References 33 publications

Polymeric iron chelators for enhancing 5‐aminolevulinic acid‐induced photodynamic therapy

Polymeric iron chelators for enhancing 5‐aminolevulinic acid‐induced photodynamic therapy

Combined Presence of Ferrous Ions and Hydrogen Peroxide in Normal Saline and In Vitro Models Induces Enhanced Aggregation of Therapeutic IgG due to Hydroxyl Radicals

Enhanced Therapeutic Applications of Vitamin C via Nanotechnology-Based Pro-Oxidant Properties: A Review

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