Acetazolamide Serves as Selective Delivery Vehicle for Dipeptide-Linked Drugs to Renal Cell Carcinoma.
Acetazolamide Serves as Selective Delivery Vehicle for Dipeptide-Linked Drugs to Renal Cell Carcinoma.
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DOI：
10.1158/1535-7163.mct-16-0283
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发表时间：
2016-12
影响因子：
5.7
通讯作者：
Neri D
中科院分区：
文献类型：
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作者：
Cazzamalli S;Dal Corso A;Neri D
在大多数情况下，细胞毒药物不会优先积聚在肿瘤部位，导致不必要的毒性，并防止剂量升级为治疗活性方案。在这里，我们展示了乙酰唑胺衍生物，它与肾癌细胞表面的碳酸酐酶IX(CAIX)结合，选择性地在病变部位运送有效载荷，而不是正常器官。在荷瘤小鼠身上进行的生物分布研究表明，在高达560nmol/kg的剂量下，乙酰唑胺衍生物携带有氚-99M络合物或红色荧光团作为有效载荷，有利于肿瘤的积累。肿瘤中每克注射剂量的百分比是剂量依赖的，最佳的肿瘤与器官的比例为140nmol/kg，肿瘤与血液的比例在6h时为80：1。乙酰唑胺通过二肽连接物与有效的细胞毒药物偶联，对荷有SKRC-52肾细胞癌的裸鼠显示出强大的抗肿瘤活性，而不含乙酰唑胺部分的药物衍生物在相同剂量下没有表现出任何可检测到的抗癌活性。用非内化配体和不同的细胞毒部分(MMAE和PNU-159682)观察肿瘤的消退表明，一般的作用机制是基于产物在肿瘤细胞上的选择性积聚，然后是细胞外蛋白分解释放肿瘤部位的细胞毒有效载荷，随后药物内化到肿瘤细胞。基于乙酰唑胺的药物结合物可能是一类很有前途的转移性肾癌的靶向药物，因为大多数人肾透明细胞癌CAIX呈强阳性。
In most cases, cytotoxic drugs do not preferentially accumulate at the tumor site, causing unwanted toxicities and preventing dose escalation to therapeutically active regimens. Here, we show that acetazolamide derivatives, which bind to carbonic anhydrase IX (CAIX) on the surface of kidney cancer cells, selectively deliver payloads at the site of disease, sparing normal organs. Biodistribution studies, performed in tumor-bearing mice with acetazolamide derivatives bearing a technetium-99m chelator complex or a red fluorophore as payload, revealed a preferential tumor accumulation of the compound at doses up to 560 nmol/Kg. The percentage of injected dose per gram in the tumor was dose-dependent and revealed optimal tumor:organ ratios at 140 nmol/Kg, with a tumor:blood ratio of 80:1 at 6 h. Acetazolamide, coupled to potent cytotoxic drugs via a dipeptide linker, exhibited a potent antitumor activity in nude mice bearing SKRC-52 renal cell carcinomas, while drug derivatives devoid of the acetazolamide moiety did not exhibit any detectable anticancer activity at the same doses. The observation of tumor regression with a noninternalizing ligand and with different cytotoxic moieties (MMAE and PNU-159682) indicates a general mechanism of action, based on the selective accumulation of the product on tumor cells, followed by the extracellular proteolytic release of the cytotoxic payload at the neoplastic site and the subsequent drug internalization into tumor cells. Acetazolamide-based drug conjugates may represent a promising class of targeted agents for the treatment of metastatic kidney cancer, as the majority of human clear cell renal cell carcinomas are strongly positive for CAIX.