State Key Laboratory of Radiation Medicine and Protection, School for Radiological and Interdisciplinary Sciences (RAD-X), and Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou 215123, P. R. China.
Laboratory of Nuclear Medicine, Ministry of Health, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi 214063, P. R. China.
ACS Appl Mater Interfaces. 2021 Dec 22;13(50):59787-59802. doi: 10.1021/acsami.1c21062. Epub 2021 Dec 13.
Developing intelligent and morphology-transformable nanomaterials that can spatiotemporally undergo stimulus-responsive size transformation holds great promise for improving the tumor delivery efficiency of drugs . Here, we report a smart size-transformable theranostic probe Ce6-Leu consisting of a leucine amino peptidase (LAP) and glutathione (GSH) dual-responsive moiety, an 1,2-aminothiol group, and a clinically used photosensitizer Ce6. This probe tends to self-assemble into uniform nanoparticles with an initial size of ∼80 nm in aqueous solution owing to the amphiphilic feature. Surprisingly, taking advantage of the biocompatible CBT-Cys condensation reaction, the large nanoprobes can be transformed into tiny nanoparticles (∼23 nm) under the joint action of LAP and GSH in a tumor microenvironment, endowing them with great tumor accumulation and deep tissue penetration. Concomitantly, this LAP/GSH-driven disassembly and size shrinkage of Ce6-Leu can also activate the fluorescence/magnetic resonance signals and the photodynamic effect for enhanced multimodal imaging-guided photodynamic therapy of human liver HepG2 tumors . More excitingly, the Mn-chelating probe (Ce6-Leu@Mn) was demonstrated to have the capability to catalyze endogenous HO to persistently release O at the hypoxic tumor site, as a consequence improving the oxygen supply to boost the radiotherapy effect. We thus believe that this LAP/GSH-driven size-transformable nanosystem would offer a novel advanced technology to improve the drug delivery efficiency for achieving precise tumor diagnosis and treatment.
开发能够时空响应刺激的智能形态可变形纳米材料，有望提高药物的肿瘤递药效率。在这里，我们报告了一种由亮氨酸氨肽酶（LAP）和谷胱甘肽（GSH）双重响应部分、1,2-氨硫醇基团和临床使用的光敏剂 Ce6 组成的智能尺寸可变形治疗探针 Ce6-Leu。由于两亲性特征，该探针在水溶液中倾向于自组装成初始尺寸约为 80nm 的均匀纳米颗粒。令人惊讶的是，利用生物相容性的 CBT-Cys 缩合反应，在肿瘤微环境中 LAP 和 GSH 的共同作用下，大纳米探针可以转化为微小的纳米颗粒（约 23nm），从而赋予它们巨大的肿瘤积累和深层组织穿透能力。同时，Ce6-Leu 的 LAP/GSH 驱动的解组装和尺寸收缩也可以激活荧光/磁共振信号和光动力效应，用于增强人肝癌 HepG2 肿瘤的多模态成像引导光动力治疗。更令人兴奋的是，Mn 螯合探针（Ce6-Leu@Mn）被证明能够在缺氧肿瘤部位持续催化内源性 HO 释放 O，从而改善氧气供应以增强放疗效果。因此，我们相信这种 LAP/GSH 驱动的尺寸可变形纳米系统将提供一种新的先进技术，以提高药物输送效率，实现精确的肿瘤诊断和治疗。
