Exploiting Cancer Vulnerabilities by Blocking of the DHODH and GPX4 Pathways: A Multifunctional Bodipy/PROTAC Nanoplatform for the Efficient Synergistic Ferroptosis Therapy,Advanced Healthcare Materials

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Exploiting Cancer Vulnerabilities by Blocking of the DHODH and GPX4 Pathways: A Multifunctional Bodipy/PROTAC Nanoplatform for the Efficient Synergistic Ferroptosis Therapy
Advanced Healthcare Materials ( IF 10.0 ) Pub Date : 2023-05-19 , DOI: 10.1002/adhm.202300871
Lang Yao _{1,

2} , Na Yang _{1,

2} , Wei Zhou _{1,

2} , Mahmood Hassan Akhtar ₁ , Weiping Zhou _{1,

2} , Chang Liu _{1,

2} , Shuang Song ₁ , Ying Li ₁ , Wenzhao Han ₁ , Cong Yu _{1,

2}

Affiliation

Ferroptosis is a form of programmed cell death and plays an important role in many diseases. Dihydroorotate dehydrogenase (DHODH) and glutathione peroxidase 4 (GPX4) play major roles in cell resistance to ferroptosis. Therefore, inactivation of these proteins provides an excellent opportunity for efficient ferroptosis-based synergistic cancer therapy. In this study, a multifunctional nanoagent (BPN_pro) containing a GPX4 targeting boron dipyrromethene (Bodipy) probe (BP) and a DHODH targeting proteolysis targeting chimera (PROTAC) is reported. BPN_pro is prepared using a nanoprecipitation method in the presence of a thermoresponsive liposome, where BP is encapsulated inside and the cathepsin B (CatB)-cleavable PROTAC peptide (DPCP) is modified on the outer surface. In the presence of near-infrared (NIR) photoirradiation, BPN_pro is melted and BP is released in tumor cells. Subsequently, BP inhibits the activity of GPX4 by covalently bonding with the selenocysteine at the enzyme active site. In addition, DPCP achieves sustained degradation of DHODH upon activation by CatB overexpressed in the tumor. The synergistic deactivation of GPX4 and DHODH induces extensive ferroptosis and subsequent cell death. In vivo and in vitro studies clearly show that the proposed ferroptosis therapy provides excellent antitumor effect.

中文翻译：

通过阻断 DHODH 和 GPX4 途径利用癌症脆弱性：用于高效协同铁死亡疗法的多功能 Bodipy/PROTAC 纳米平台

铁死亡是程序性细胞死亡的一种形式，在许多疾病中发挥着重要作用。二氢乳清酸脱氢酶 (DHODH) 和谷胱甘肽过氧化物酶 4 (GPX4) 在细胞抵抗铁死亡中发挥着重要作用。因此，这些蛋白质的失活为有效的基于铁死亡的协同癌症治疗提供了极好的机会。在这项研究中，报道了一种多功能纳米剂（BPN _{pro ），其中含有GPX4靶向硼二吡咯亚甲基（Bodipy）探针（BP）和DHODH靶向蛋白水解靶向嵌合体（PROTAC）。}BPN _pro采用纳米沉淀法在热响应性脂质体存在下制备，其中 BP 封装在内部，组织蛋白酶 B (CatB) 可裂解的 PROTAC 肽 (DPCP) 在外表面进行修饰。在近红外 (NIR) 光照射下，BPN _pro被熔化，并在肿瘤细胞中释放 BP。随后，BP 通过与酶活性位点的硒代半胱氨酸共价结合来抑制 GPX4 的活性。此外，DPCP 在肿瘤中过表达的 CatB 激活后可实现 DHODH 的持续降解。GPX4 和 DHODH 的协同失活会诱导广泛的铁死亡和随后的细胞死亡。体内和体外研究清楚地表明，所提出的铁死亡疗法具有优异的抗肿瘤效果。

更新日期：2023-05-19

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