We have previously reported the in vitro and in vivo efficacy of N,N-bis(2-chloroethyl)-2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)propenamide (MP-MUS), a prodrug that targeted the mitochondria of glioblastoma (GBM). The mitochondrial enzyme, monoamine oxidase B (MAOB), is highly expressed in GBM and oxidizes an uncharged methyl-tetrahydropyridine (MP-) moiety into the mitochondrially targeted cationic form, methyl-pyridinium (P+-). Coupling this MAOB-sensitive group to a nitrogen mustard produced a prodrug that damaged GBM mitochondria and killed GBM cells. Unfortunately, the intrinsic reactivity of the nitrogen mustard group and low solubility of MP-MUS precluded clinical development. In our second-generation prodrug, MP-Pt(IV), we coupled the MP group to an unreactive cisplatin precursor. The enzymatic conversion of MP-Pt(IV) to P+-Pt(IV) was tested using recombinant human MAOA and rhMAOB. The generation of cisplatin from Pt(IV) by ascorbate was studied optically and using mass spectroscopy. Efficacy toward primary GBM cells and tumors was studied in vitro and in an intracranial patient-derived xenograft mice GBM model. Our studies demonstrate that MP-Pt(IV) is selectively activated by MAOB. MP-Pt(IV) is highly toxic toward GBM cells in vitro. MP-Pt(IV) toxicity against GBM is potentiated by elevating mitochondrial ascorbate and can be arrested by MAOB inhibition. In in vitro studies, sublethal MP-Pt(IV) doses elevated mitochondrial MAOB levels in surviving GBM cells. MP-Pt(IV) is a potent chemotherapeutic in intracranial patient-derived xenograft mouse models of primary GBM and potentiates both temozolomide and temozolomide–chemoradiation therapies. MP-Pt(IV) was well tolerated and is highly effective against GBM in both in vitro and in vivo models.

中文翻译：

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MP-Pt(IV)：一种 MAOB 敏感的线粒体特异性前药，用于治疗胶质母细胞瘤

我们之前曾报道过 N,N-双(2-氯乙基)-2-(1-甲基-1,2,3,6-四氢吡啶-4-基)丙烯酰胺 (MP-MUS) 的体外和体内功效，一种靶向胶质母细胞瘤（GBM）线粒体的前药。线粒体酶单胺氧化酶 B (MAOB) 在 GBM 中高度表达，并将不带电荷的甲基四氢吡啶 (MP-) 部分氧化成线粒体靶向的阳离子形式甲基吡啶鎓 (P+-)。将这个 MAOB 敏感组与氮芥偶联产生一种前药，可破坏 GBM 线粒体并杀死 GBM 细胞。不幸的是，氮芥基团的固有反应性和 MP-MUS 的低溶解度阻碍了临床开发。在我们的第二代前药 MP-Pt(IV) 中，我们将 MP 基团与无反应的顺铂前体偶联。使用重组人 MAOA 和 rhMAOB 测试了 MP-Pt(IV) 到 P+-Pt(IV) 的酶促转化。用光学和质谱法研究了抗坏血酸从 Pt(IV) 生成顺铂。在体外和颅内患者来源的异种移植小鼠 GBM 模型中研究了对原代 GBM 细胞和肿瘤的功效。我们的研究表明 MP-Pt(IV) 被 MAOB 选择性激活。MP-Pt(IV) 在体外对 GBM 细胞具有高毒性。MP-Pt(IV) 对 GBM 的毒性通过提高线粒体抗坏血酸而增强，并且可以通过 MAOB 抑制来阻止。在体外研究中，亚致死 MP-Pt(IV) 剂量会提高幸存的 GBM 细胞中线粒体 MAOB 的水平。MP-Pt(IV) 是一种有效的化疗药物，可用于原发性 GBM 的颅内患者来源的异种移植小鼠模型，并增强替莫唑胺和替莫唑胺放化疗的疗效。MP-Pt(IV) 具有良好的耐受性，并且在体外和体内模型中对 GBM 非常有效。