谷胱甘肽响应的近红外二b区荧光探针用于荧光成像引导手术切除和光热治疗的研究

The second b near-infrared window fluorescence (NIR IIb, 1500-1700 nm) has overwhelming advantages for deep tumor and metastase bioimaging identification, due to deeper penetration depth and higher signal to noise ratio. However, the low quantum yield, low tumor specificity and high toxicity of current NIR IIb fluorescent probes impede the efficient and sensitive detection of deep tumors and metastases. Therefore, in this project, the hollow virus-like mesoporous organosilica with tetrasulfide groups are coated on the out layer of PbS@Cd quantum dots, to build the NIR IIb complex nanoprobes with high tumor specificity, high quantum yield and low toxicity in vivo. This nanoprobes also loaded with the near-infrared organic probe, IR820; owing to the absorption competition induced emission, the PbS@CdS has no fluorescence in normal tissues. While, PbS@CdS can emit 1650 nm NIR-II fluorescence for efficient and specific NIR IIb fluorescent bioimaging guided tumor surgery which could greatly enhance thoroughness of surgery. This is mainly because the tetrasulfide groups in virus-like mesoporous organosilica can degrade by the high content of glutathione in tumor microenvironment and to release IR820. Meanwhile, the released IR820 is capable of inhibit distal metastases after photothermal therapy under NIR IIb fluorescence bioimaging guidance, to increase the thoroughness of tumor inhibition, therefore to improve the long-term survival of patients.

近红外二b区（NIR IIb, 1500-1700 nm）波段的荧光探针由于更深的穿透深度、更高的信噪比，在探测深层肿瘤的成像上更具有优势。然而，当前NIR IIb探针存在量子产率低、肿瘤的特异性差和生物毒性大等问题，阻碍了其高灵敏的探测深层肿瘤和转移灶。为此，本项目利用空心病毒介孔有机硅包裹PbS@CdS量子点构筑肿瘤微环境特异响应、高量子产率、低毒性的NIR IIb复合纳米探针。该复合探针可以负载近红外染料IR820，在正常组织中，通过竞争吸收作用，量子点不发光；在肿瘤细胞中，病毒有机硅壳层中的四硫键可以被肿瘤微环境中谷胱甘肽降解，触发释放出负载的IR820，从而量子点可以发出1650 nm的荧光用于高效特异的NIR IIb荧光成像引导的肿瘤手术切除，增加手术彻底性。此外，IR820还可以用于远端转移灶的NIR IIb荧光成像指导的光热治疗，增加治疗彻底性，提高病人的远期生存。

受本基金项目资助，项目负责人王培园发表SCI论文13篇，包括Biomaterials、Advanced Science、Chemical Engineering Journal、Advanced Healthcare Materials、Materials Today Bio等；申请发明专利2项。受本基金项目资助，联合培养毕业博士2名，硕士1名；在读博士1名，在读硕士3名。.本项目针对当前近红外二区(NIR II, 1000-1700 nm) 探针量子产率低、肿瘤特异性差、生物安全性低的等问题，拟设计合成安全性高的新型肿瘤微环境响应性NIR II复合探针，实现肿瘤成像时信噪比的极大增强，提高NIR II荧光成像导航肿瘤切除的精准性和远端转移灶的彻底抑制。本项目在执行期间根据计划顺利推进相关研究，完成了项目的所有预期目标。取得的原创性成果主要包括：1) 设计合成出系列生物相容性强、量子产率高、光稳定性强的NIR II探针，完成了后续的功能化修饰和装载，验证了新型NIR II复合探针肿瘤微环境响应性的性能; 2) 验证了系列探针对活体肿瘤精准的靶向性、富集性以及NIR II荧光信噪比的响应性增强；3) 在小动物体内进行NIR II荧光成像引导实体肿瘤的切除，通过病理分析验证了外科切除的精准性，术后28天，未发现任何原位复发和多器官转移；4) 该系列复合探针还具备多模式治疗的性能，对于远端转移灶，实现了NIR II荧光成像指导的光热/化动力/放疗/光动力治疗，增加肿瘤治疗的彻底性。