GSH/HAase/pH三重响应纳米诊疗剂用于肿瘤靶向荧光/光声双模成像指导的协同治疗
收稿日期: 2024-04-05
网络出版日期: 2024-08-12
基金资助
江苏高校优势学科建设工程项目、先进生物与化学制造国家协同创新中心及有机电子与信息显示国家重点实验室开放研究基金资助
GSH/HAase/pH Triple-responsive Nanotheranostic Agent for Synergistic Therapy Guided by Tumor-targeting Fluorescence/Photoacoustic Dual-mode Imaging
Received date: 2024-04-05
Online published: 2024-08-12
Supported by
Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD), the Jiangsu National Synergetic Innovation Center for Advanced Materials (SICAM), and the open research fund of State Key Laboratory of Organic Electronics and Information Displays
本工作构建了一种多功能纳米诊疗剂FePDA/DOX@HA-CYS-TTDPP, 用于肿瘤靶向荧光/光声双模态成像指导的光疗/化学动力学治疗/化疗协同治疗. 将近红外吸收的吡咯并吡咯二酮衍生物(TTDPP)通过胱胺(CYS)与肿瘤靶向生物大分子透明质酸(HA)偶联, 得到两亲性聚合物HA-CYS-TTDPP; 再与Fe3+配位的聚多巴胺纳米粒子(FePDA)以及抗肿瘤药物阿霉素(DOX)进行分子自组装, 形成该纳米材料. 其光热转换效率达到65.6%, 且具有良好的光声性能, 这归因于TTDPP和PDA良好的光热转换性能, 且Fe3+进一步增强了PDA的光热效应; 它还可以对肿瘤微环境的弱酸性pH值、过表达的谷胱甘肽(GSH)和透明质酸酶(HAase)产生三重响应, 实现靶向药物控释和荧光激活; Fe3+能与肿瘤中的 GSH和H2O2引发芬顿反应, 生成具有细胞毒性的•OH, 从而产生化学动力学治疗性能. 细胞实验证实FePDA/DOX@HA-CYS-TTDPP能够智能响应肿瘤微环境而实现靶向荧光成像, 并通过光疗/化学动力学治疗/化疗协同治疗有效抑制HeLa肿瘤细胞的增殖. 该体系为实现精准高效的肿瘤诊疗拓展了思路.
黄艳琴 , 罗集文 , 李佳启 , 张瑞 , 刘兴奋 , 范曲立 , 黄维 . GSH/HAase/pH三重响应纳米诊疗剂用于肿瘤靶向荧光/光声双模成像指导的协同治疗[J]. 化学学报, 2024 , 82(8) : 903 -913 . DOI: 10.6023/A24040115
In this work, a multifunctional nanotheranostic agent FePDA/DOX@HA-CYS-TTDPP was constructed for photo/chemodynamic/chemo synergistic therapy guided by tumor-targeting fluorescence/photoacoustic dual-mode imaging. The diketopyrrolopyrrole (DPP) derivative (TTDPP) with near-infrared (NIR) absorption was coupled with tumor-targeting biomolecule hyaluronic acid (HA) via cystamine (CYS) to obtain the amphiphilic polymer HA-CYS-TTDPP. It was then self-assembled with Fe3+-coordinated polydopamine nanoparticles (FePDA) and anti-tumor drug doxorubicin (DOX) to form this nanomaterial. Its photothermal conversion efficiency reached 65.6% and it showed good photoacoustic performance, which can be attributed to the excellent photothermal conversion performance of TTDPP and PDA. TTDPP was a D-π-A-π-D type DPP derivative formed by the electron acceptor (A) DPP, the electron donor (D) triphenylamine, and the conjugated bridge thiophene, which exhibited excellent photothermal and photoacoustic performance, and a certain degree of photodynamic effect. PDA was formed by dopamine oxidation self-polymerization, which showed the advantages of good biocompatibility, high photothermal conversion efficiency, and easy functionalization; moreover, due to the d-d transition of exogenous Fe3+ in FePDA, the photothermal effect of PDA can be further enhanced. Furthermore, the weak acidity of tumor microenvironment (TME) facilitated the dissolution and release of DOX, and the overexpressed hyaluronidase (HAase) and glutathione (GSH) in tumor cells can also trigger the degradation of HA and the cleavage of disulfide bonds in CYS, respectively, leading to the release of DOX. Thus, the distance between DOX and PDA and TTDPP was increased, and the fluorescence of DOX was recovered, thereby achieving TME-responsive fluorescence activation and controlled drug release, and the tumor-targeting effect was further enhanced. Therefore, this nanotheranostic agent can realize triple response to the weak acidity, overexpressed GSH and HAase of TME. On the other hand, Fe3+ can react with GSH and H2O2 in tumor cells to induce Fenton reaction, generating cytotoxic •OH and resulting in chemodynamic therapeutic performance. Cell experiments confirmed that FePDA/DOX@HA-CYS-TTDPP can intelligently respond to TME and achieve targeted fluorescence imaging, and effectively inhibit the proliferation of HeLa tumor cells through photo/chemodynamic/chemo synergistic therapy. This system provides new ideas for achieving precise and efficient tumor theranostics.
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