γ-Glutamyl transpeptidase-activatable near-infrared nanoassembly for tumor fluorescence imaging-guided photothermal therapy.
γ-Glutamyl transpeptidase-activatable near-infrared nanoassembly for tumor fluorescence imaging-guided photothermal therapy.
复制标题
用于肿瘤荧光成像引导光热治疗的γ-谷氨酰转肽酶激活近红外纳米组件
作者：
Zhou F;Yang S;Zhao C;Liu W;Yao X;Yu H;Sun X;Liu Y
理论基础：肿瘤的精确治疗正引起越来越多的关注。同时显示肿瘤微环境的诊断信号和药理作用的分子探针是人们迫切需要的。谷氨酰转肽酶(γ-Glamyl Transspeptidase，GGT)是一种在肿瘤组织中显著上调表达的生物标志物。我们开发了一种GGT响应性近红外(NIR)纳米组件，用于肿瘤特异性荧光成像引导的光热治疗。方法：通过酰胺反应将谷氨酸特异性底物γ-谷氨酸(γ-Glu)与氰基荧光团(NRH-NH_2)偶联，构建了GGT响应型近红外探针。生成的NRH-G自发组装成约50 nm的纳米颗粒(NRH-G-NPs)。在GGT存在或不存在的情况下，对NPs进行了表征和性能评价。随后，我们对NRH-G-NPs的体内外荧光成像和光热治疗进行了研究。结果：NRH-G-NPs与GGT特异性反应生成NRH-NH2-NPs，荧光增强约180倍，光热效应恢复良好。NRH-G-NPs能选择性地发光U87 MG肿瘤细胞，而其在L02人正常肝细胞中的荧光较弱。纳米粒子在激光照射下也表现出良好的肿瘤细胞消融效果。在静脉注射到荷瘤小鼠体内后，NRH-G-NPs可以到达肿瘤区域，并特异性地照亮肿瘤。激光照射后，肿瘤可被完全清除，40天内不会复发。结论：NRH-G-NPs对GGT在U87 MG肿瘤细胞中的高表达具有特异性反应，并选择性地照亮肿瘤进行影像引导治疗。此外，肿瘤区域光热性质的恢复可以提高肿瘤治疗的精确度，减少对正常组织的副作用。
Rationale: Precise treatment of tumors is attracting increasing attention. Molecular probes simultaneously demonstrating the diagnostic signal and pharmacological effect in response to tumor microenvironment are highly desired. γ-glutamyl transpeptidase (GGT) is a biomarker with significantly up-regulated expression in the tumor area. We developed a GGT responsive near-infrared (NIR) nanoassembly for tumor-specific fluorescence imaging-guided photothermal therapy. Methods: The GGT responsive NIR probe was constructed by conjugating GGT-specific substrate γ-glutamic acid (γ-Glu) with cyanine fluorophore (NRh-NH2) via amide reaction. The resulting NRh-G spontaneously assembled into nanoparticles (NRh-G-NPs) around 50 nm. The NPs were characterized and the properties evaluated in the presence or absence of GGT. Subsequently, we studied fluorescence imaging and photothermal therapy of NRh-G-NPs in vitro and in vivo. Results: NRh-G-NPs, upon specific reaction with GGT, turned into NRh-NH2-NPs, showing a ~180-fold fluorescence enhancement and excellent photothermal effect recovery. NRh-G-NPs could selectively light up U87MG tumor cells while their fluorescence was weak in L02 human normal liver cells. The NPs also showed excellent tumor cell ablation upon laser irradiation. After intravenous injection into tumor-bearing mice, NRh-G-NPs could arrive in the tumor area and specifically light up the tumor. Following laser irradiation, the tumor could be completely erased with no tumor reoccurrence for up to 40 days. Conclusions: NRh-G-NPs were specifically responsive to GGT overexpressed in U87MG tumor cells and selectively lit up the tumor for imaging-guided therapy. Besides, the recovery of photothermal property in the tumor area could improve cancer therapy precision and decreased side effects in normal tissues.