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首页> 外文期刊>RSC Advances >RGD-modified dihydrolipoamide dehydrogenase conjugated to titanium dioxide nanoparticles – switchable integrin-targeted photodynamic treatment of melanoma cells
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RGD-modified dihydrolipoamide dehydrogenase conjugated to titanium dioxide nanoparticles – switchable integrin-targeted photodynamic treatment of melanoma cells

机译：RGD修饰的二氢脂酰胺脱氢酶与二氧化钛纳米粒子结合–可调节的整合素靶向光动力学治疗黑素瘤细胞

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The photocytotoxic effect of UVA-excited titanium dioxide (TiO _(2) ), which is caused by the generation of reactive oxygen species (ROS), is often used in medical applications, such as cancer treatment. Photodynamic-therapy (PDT) is applied in several cancer models including cutaneous melanoma (CM), however the lack of selectivity causing damage to surrounding healthy tissues limits its applicability and novel targeted-delivery approaches are required. As cancer cells often overexpress integrin receptors ( e.g. αvβ _(3) ) on their cell surface, targeted delivery of TiO _(2) nanoparticles (NPs) via an Arg-Gly-Asp (RGD) motif would make PDT more selective. We have recently reported that the mitochondrial enzyme dihydrolipoamide dehydrogenase (DLDH) strongly and specifically conjugates TiO _(2) via coordinative bonds. In this work we have modified DLDH with RGD moieties (DLDH ~(RGD) ), creating a molecular bridge between the integrin-expressing cancer cells and the photo-excitable TiO _(2) nanoparticles. Physicochemical assays have indicated that the hybrid-conjugated nanobiocomplex, TiO _(2) –DLDH ~(RGD) , is producing controlled-release ROS under UVA illumination, with anatase NPs being the most photoreactive TiO _(2) form. This drug delivery system exhibited a cytotoxic effect in αvβ _(3) integrin-expressing mice melanoma cells (B16F10), but not in normal cells lacking this integrin (HEK293). No cytotoxic effect was observed in the absence of UV illumination. Our results demonstrate the feasibility of combining the high efficiency of TiO _(2) -based PDT, with an integrin-mediated tumor-targeted drug delivery for nanomedicine.
机译：UVA激发的二氧化钛（TiO_（2））的光细胞毒性作用是由活性氧（ROS）的产生引起的，通常用于医学应用，例如癌症治疗。光动力疗法（PDT）已在包括皮肤黑素瘤（CM）在内的多种癌症模型中应用，但是选择性缺乏导致对周围健康组织的损害限制了其适用性，因此需要新颖的靶向递送方法。由于癌细胞通常会在其细胞表面过表达整联蛋白受体（例如αvβ_（3）），因此通过Arg-Gly-Asp（RGD）基序有针对性地传递TiO_（2）纳米粒子（NPs）将使PDT更具选择性。最近，我们报道了线粒体酶二氢脂酰胺脱氢酶（DLDH）通过配位键强烈而特异性地共轭TiO_（2）。在这项工作中，我们用RGD部分（DLDH〜（RGD））修饰了DLDH，在表达整联蛋白的癌细胞和可光激发的TiO_（2）纳米粒子之间建立了分子桥梁。理化分析表明，杂化共轭纳米生物复合物TiO_（2）–DLDH〜（RGD）在UVA照射下产生控释ROS，锐钛矿型NPs是最光反应性的TiO_（2）形式。该药物递送系统在表达αvβ_（3）整合素的小鼠黑素瘤细胞（B16F10）中显示出细胞毒性作用，但在缺乏该整合素的正常细胞（HEK293）中则没有。在没有紫外线照射下没有观察到细胞毒性作用。我们的结果证明了将基于TiO _（2）的PDT的高效率与整合素介导的靶向肿瘤的纳米药物递送相结合的可行性。

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