Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.
Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.
Angew Chem Int Ed Engl. 2017 Aug 21;56(35):10418-10422. doi: 10.1002/anie.201704793. Epub 2017 Jul 28.
We adopted a spirocyclization-based strategy to design γ-glutamyl hydroxymethyl selenorhodamine green (gGlu-HMSeR) as a photo-inactive compound that would be specifically cleaved by the tumor-associated enzyme γ-glutamyltranspeptidase (GGT) to generate the potent photosensitizer HMSeR. gGlu-HMSeR has a spirocyclic structure and is colorless and does not show marked phototoxicity toward low-GGT-expressing cells or normal tissues upon irradiation with visible light. In contrast, HMSeR predominantly takes an open structure, is colored, and generates reactive oxygen species upon irradiation. The γ-glutamyl group thus serves as a tumor-targeting moiety for photodynamic therapy (PDT), switching on tumor-cell-specific phototoxicity. To validate this system, we employed chick chorioallantoic membrane (CAM), a widely used model for preliminary evaluation of drug toxicity. Photoirradiation after gGlu-HMSeR treatment resulted in selective ablation of implanted tumor spheroids without damage to healthy tissue.
我们采用基于螺环化的策略设计γ-谷氨酰羟甲基硒代罗丹明绿（gGlu-HMSeR）作为一种光惰性化合物，该化合物可被肿瘤相关酶γ-谷氨酰转肽酶（GGT）特异性切割，生成有效的光敏剂 HMSeR。gGlu-HMSeR 具有螺环结构，为无色，在可见光照射下对低表达 GGT 的细胞或正常组织没有明显的光毒性。相比之下，HMSeR 主要呈开环结构，有颜色，并在照射时产生活性氧。因此，γ-谷氨酰基作为光动力疗法（PDT）的肿瘤靶向部分，开启肿瘤细胞特异性光毒性。为了验证该系统，我们使用了鸡胚尿囊膜（CAM），这是一种广泛用于初步评估药物毒性的模型。gGlu-HMSeR 处理后进行光照射导致植入的肿瘤球体选择性消融，而健康组织不受损伤。
