Self-Immolative nanoparticles for stimuli-triggered activation, covalent trapping and accumulation of in situ generated small molecule theranostic fragments
Self-Immolative nanoparticles for stimuli-triggered activation, covalent trapping and accumulation of in situ generated small molecule theranostic fragments
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用于刺激触发激活、共价捕获和原位生成小分子治疗片段积累的自焚纳米颗粒
DOI：
10.1016/j.giant.2020.100012
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发表时间：
2020-03-01
期刊：
影响因子：
7
通讯作者：
Liu, Shiyong
中科院分区：
文献类型：
--
作者：
Ding, Zexuan;Cen, Jie;Liu, Shiyong
小分子治疗诊断剂具有快速血液清除的缺点，而纳米颗粒治疗诊断剂不能发挥分子功能并且通常是不可降解的。我们建议弥合纳米颗粒和小分子试剂之间的差距的基础上，在链水平上发生触发级联解聚的自分解聚合物。含有侧链官能化可解聚嵌段的两亲性嵌段共聚物自组装成胶束纳米颗粒。在用活性氧（ROS）和酸性pH触发时，纳米颗粒自分解成缺电子小分子氮喹酮甲基化物（AQM）衍生物，其能够与生物学相关的亲核试剂进行有效的加成反应。利用这一特性，我们实现了刺激激活的F-19 NMR/MR成像和F-19/H-1双模态MR成像。细胞摄入后，解聚过程中产生的AQM与细胞内巯基相关底物（包括GSH和含巯基蛋白质）发生反应。从DOTA-Gd功能化的自分解纳米颗粒开始，我们通过原位共价捕获策略展示了前所未有的荷瘤小鼠体内长期H-1 MR成像。
Small molecule theranostic agents suffer from fast blood clearance whereas nanoparticle ones are incapable of molecular functions and often nondegradable. We propose to bridge the gap between nanoparticles and small molecule agents based on self-immolative polymers which undergo triggered cascade depolymerization at the chain level. Amphiphilic block copolymers containing side chain-functionalized depolymerizable block self-assemble into micellar nanoparticles. Upon triggering with reactive oxygen species (ROS) and acidic pH, nanoparticles self-immolate into electron-deficient small molecule azaquinone methide (AQM) derivatives, which are capable of efficient addition reactions with biologically relevant nucleophiles. By taking advantage of this feature, we achieve stimuli-activatable F-19 NMR/MR imaging and F-19/H-1 dual-modality MR imaging. Upon cellular uptake, AQMs generated during depolymerization react with intracellular thiol-relevant substrates including GSH and thiol-containing proteins. Starting from self-immolative nanoparticles functionalized with DOTA-Gd, we demonstrate unprecedented long-term in vivo H-1 MR imaging of tumor-bearing mice via the in situ covalent trapping strategy.