Trojan Horse for Light-Triggered Bifurcated Production of Singlet Oxygen and Fenton-Reactive Iron within Cancer Cells,Biomacromolecules

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Trojan Horse for Light-Triggered Bifurcated Production of Singlet Oxygen and Fenton-Reactive Iron within Cancer Cells
Biomacromolecules ( IF 5.5 ) Pub Date : 2017-12-14 00:00:00 , DOI: 10.1021/acs.biomac.7b01433
Daniela Cioloboc ₁ , Christopher Kennedy ₁ , Emily N. Boice ₁ , Emily R. Clark ₁ , Donald M. Kurtz ₁

Affiliation

Traditional photodynamic therapy for cancer relies on dye-photosensitized generation of singlet oxygen. However, therapeutically effective singlet oxygen generation requires well-oxygenated tissues, whereas many tumor environments tend to be hypoxic. We describe a platform for targeted enhancement of photodynamic therapy that produces singlet oxygen in oxygenated environments and hydroxyl radical, which is typically regarded as the most toxic reactive oxygen species, in hypoxic environments. The 24-subunit iron storage protein bacterioferritin (Bfr) has the unique property of binding 12 heme groups in its protein shell. We inserted the isostructural photosensitizer, zinc(II) protoporphyrin IX (ZnP), in place of the hemes and extended the surface-exposed N-terminal ends of the Bfr subunits with a peptide targeting a receptor that is hyperexpressed on the cell surface of many tumors and tumor vasculature. We then loaded the inner cavity with ∼2500 irons as a ferric oxyhydroxide polymer and finally conjugated 2 kDa polyethylene glycol to the outer surface. We showed that the inserted ZnP photosensitizes generation of both singlet oxygen and the hydroxyl radical, the latter via the reaction of photoreleased ferrous iron with hydrogen peroxide. This targeted iron-loaded ZnP-Bfr construct was endocytosed by C32 melanoma cells and localized to lysosomes. Irradiating the treated cells with light at wavelengths overlapping the ZnP Soret absorption band induced photosensitized intracellular Fe²⁺ release and substantial lowering of cell viability. This targeted, light-triggered production of intracellular singlet oxygen and Fenton-reactive iron could potentially be developed into a phototherapeutic adjunct for many types of cancers.

中文翻译：

特洛伊木马在癌细胞内轻触发分叉产生单线态氧和Fenton反应铁

传统的癌症光动力疗法依赖于染料光敏化单线态氧的产生。然而，治疗有效的单线态氧的产生需要氧合良好的组织，而许多肿瘤环境往往是低氧的。我们描述了针对性的光动力疗法增强平台，该平台在含氧环境中产生单线态氧和在低氧环境中通常被认为是毒性最强的活性氧种类的羟基自由基。具有24个亚基的铁存储蛋白细菌铁蛋白（Bfr）具有在其蛋白壳中结合12个血红素基团的独特特性。我们插入了同种结构的光敏剂锌原卟啉IX（ZnP），代替血红素，并用靶向许多细胞和肿瘤脉管系统细胞表面过表达的受体的肽扩展Bfr亚基的表面暴露N末端。然后，我们在内部空腔中装入约2500个铁作为羟基氧化铁聚合物，最后将2 kDa聚乙二醇共轭到外表面。我们表明，插入的ZnP通过光释放的亚铁与过氧化氢的反应使单线态氧和羟基自由基产生光敏性。这种靶向铁负载的ZnP-Bfr构建体被C32黑色素瘤细胞内吞并定位于溶酶体。用波长与ZnP Soret吸收带重叠的光照射处理过的细胞，诱导光敏的细胞内铁然后，我们向内腔加载约2500个铁作为羟基氧化铁聚合物，最后将2 kDa聚乙二醇共轭到外表面。我们表明，插入的ZnP通过光释放的亚铁与过氧化氢的反应使单线态氧和羟基自由基产生光敏性。这种靶向铁负载的ZnP-Bfr构建体被C32黑色素瘤细胞内吞并定位于溶酶体。用波长与ZnP Soret吸收带重叠的光照射处理过的细胞，诱导光敏的细胞内铁然后，我们在内部空腔中装入约2500个铁作为羟基氧化铁聚合物，最后将2 kDa聚乙二醇共轭到外表面。我们表明，插入的ZnP通过光释放的亚铁与过氧化氢的反应使单线态氧和羟基自由基产生光敏性。这种靶向铁负载的ZnP-Bfr构建体被C32黑色素瘤细胞内吞并定位于溶酶体。用波长与ZnP Soret吸收带重叠的光照射处理过的细胞，诱导光敏的细胞内铁后者是通过光释放的亚铁与过氧化氢的反应来实现的。这种靶向铁负载的ZnP-Bfr构建体被C32黑色素瘤细胞内吞并定位于溶酶体。用波长与ZnP Soret吸收带重叠的光照射处理过的细胞，诱导光敏的细胞内铁后者是通过光释放的亚铁与过氧化氢的反应来实现的。这种靶向铁负载的ZnP-Bfr构建体被C32黑色素瘤细胞内吞并定位于溶酶体。用波长与ZnP Soret吸收带重叠的光照射处理过的细胞，诱导光敏的细胞内铁²⁺释放并显着降低细胞活力。这种有针对性的，光触发的细胞内单线态氧和Fenton反应性铁的产生可能会发展为多种类型癌症的光疗辅助剂。

更新日期：2017-12-14

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