Lv Peng-Cheng, Roy Jyoti, Putt Karson S, Low Philip S
Institute for Drug Discovery, Purdue University, West Lafayette, Indiana.
Department of Chemistry, Purdue University, West Lafayette, Indiana.
Mol Cancer Ther. 2017 Mar;16(3):453-460. doi: 10.1158/1535-7163.MCT-16-0537. Epub 2016 Dec 15.
The majority of tumors contain regions of hypoxia, which cause marked phenotypic changes to resident cells. This altered gene expression often leads to increased resistance to anticancer treatments. Therefore, elimination of these resistant hypoxic cells is crucial to prevent disease recurrence. Herein, we describe the selective delivery of imaging and chemotherapeutic agents to cells expressing carbonic anhydrase IX (CA IX), a highly upregulated hypoxia receptor. These agents were conjugated to a potent divalent CA IX ligand through a hydrophilic PEG linker. These conjugates are shown to bind CA IX-expressing cells in a receptor-dependent manner with mid-nanomolar affinities and with good tumor selectivity. In a mouse xenograft tumor model using HT-29 cells, a cytotoxic tubulysin B conjugate completely inhibited tumor growth. Overall, the targeting of a hypoxia marker, such as CA IX, to selectively deliver imaging or chemotherapeutic agents may lead to better treatment options for solid, hypoxic tumors. In addition, the combination of standard chemotherapeutics that are most potent in normoxic dividing cells and drugs specifically designed to eliminate hypoxic nondividing cells may elicit a superior clinical outcome. .
大多数肿瘤都含有缺氧区域，这会导致驻留细胞发生显著的表型变化。这种基因表达的改变通常会导致对抗癌治疗的耐药性增加。因此，消除这些耐药性缺氧细胞对于预防疾病复发至关重要。在此，我们描述了将成像剂和化疗药物选择性递送至表达碳酸酐酶IX（CA IX）的细胞，CA IX是一种高度上调的缺氧受体。这些药物通过亲水性聚乙二醇（PEG）接头与一种有效的二价CA IX配体偶联。这些偶联物显示以受体依赖性方式与表达CA IX的细胞结合，亲和力为中纳摩尔级别，且具有良好的肿瘤选择性。在使用HT - 29细胞的小鼠异种移植肿瘤模型中，一种细胞毒性微管溶素B偶联物完全抑制了肿瘤生长。总体而言，靶向缺氧标志物（如CA IX）以选择性递送成像剂或化疗药物可能会为实体缺氧肿瘤带来更好的治疗选择。此外，在常氧分裂细胞中最有效的标准化疗药物与专门设计用于消除缺氧非分裂细胞药物的联合使用可能会产生更好的临床结果。
