Cyclic enhancement of hypoxic microenvironment via an intelligent nanoamplifier for activated NIR-II fluorescence/photoacoustic imaging-guided precise synergistic therapy. (15th December 2022)

• Record Type: Journal Article
• Authors: Zheng, Ziliang; Chen, Xuejiao; Dai, Rong; Wu, Shutong; Kang, Weiwei; Qin, YuFei; Ren, Shilei; Zhang, Ruiping; Cheng, Zhen
• Is Part Of: Materials today bio. Volume 17(2023)
• Publication Date: 2022-12-15
• Subjects: Second near-infrared window -- Dual-modal imaging -- Activatable NIR-II FL Imaging -- Tumor hypoxia -- Synergistic tumor therapy; Materials science -- Periodicals; Biomedical engineering -- Periodicals; Biomedical materials -- Periodicals; 620.1
• DOI: 10.1016/j.mtbio.2022.100478
• Languages: English
• ISSNs: 2590-0064

Abstract

Abstract: Tumor microenvironment (TME)-activated theranostics is a promising strategy to effectively identify small lesions, improve antitumor efficacy, and reduce the risk of undesired side effects. Hypoxia, as a common characteristic of TME, can serve as a preferred site for stimulus-dependent activation; however, tumor-hypoxia levels in various developmental stages exhibit different characteristics, severely limiting the response sensitivity. Herein, a circulating self-reinforcing hypoxic nanoamplifier (CGH NAs) is developed that utilizes a dual-chain reaction process (internal regulation, internal regulation) to achieve precise activation of NIR-II FL/photoacoustic (PA) imaging-guided synergistic therapy. Inspired by the positive correlation of nitroreductase (NTR) with hypoxia, the CGH NAs encapsulate CQ4T and GOx into NTR-sensitive hyaluronic acid-nitroimidazole (HA-NI) shell via a self-assembly approach, enabling aggregation-caused NIR-II FL quenching and tumor-accurate delivery. When CGH NAs efficiently accumulated in the tumor region, the intensive local NTR reduced hydrophobic –NO2 to hydrophilic –NH2, which lead to disassembly of CGH NAs. The released GOx could consume O2 (internal regulation) and glucose to cut off the energy supply, inducing tumor-starvation therapy; generate gluconic acid and H2 O2 (oxidative stress). Meanwhile, the released CQ4T promoted rapid recovery of NIR-II FL signals for imaging-guided PDT, which could simultaneously deplete intratumoral O2 (external stimulation). Remarkably, the strengthened tumor-hypoxia levels in turn accelerated the NTR-responsive degradation of the CGH NAs, thereby achieving high-efficiency theranostic. Graphical abstract: In this work, a novel "internal regulation, internal regulation" dual sensitization strategy to construct a cyclically enhanced NTR-responsive nanoamplifier CGH NAs for achieving activatable NIR-Ⅱ NIR-II FL/PA imaging-guided oxidative stress/starvation/PDT combination therapy is designed. The dual-chain reaction process could in situ aggravated the hypoxic levels to enhance the NTR-response activity in the tumor region effectively, which might represent a promising intelligent nanomedicine in precision cancer theranostics. Image 1 Highlights: The cyclically enhanced NTR-responsive CGH NAs possess a dual sensitization strategy for precision tumor theranostics. The CGH NAs utilize the "internal regulation and external stimulation" dual-mechanism to amplify the hypoxia response cyclically, realizing a self-promoting degradation process. The enhanced intratumoral hypoxia levels can positively feedback-regulate to achieve precise release of GOx and CQ4T for "turn on" NIR-II FL imaging and oxidative stress/starvation/PDT combination therapy.