Zhang Wenxia, Qiao Hui, Cui Jicheng, Zhang Dongmei, Li Yingqi
Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education, Institute of Molecular Science, Shanxi University, Taiyuan 030006, PR China.
Taiyuan Central Hospital, Taiyuan 030009, PR China.
Int J Biol Macromol. 2025 May;310(Pt 4):143465. doi: 10.1016/j.ijbiomac.2025.143465. Epub 2025 Apr 23.
The tumor microenvironment poses significant challenges to reactive oxygen species treatment, and fails to retain small molecule drugs for extended periods, leading to low treatment efficacy. Here, a hyaluronic acid-based nanoplatform (HCCD) for combined chemotherapy and photodynamic therapy (PDT) is developed. The nanoplatform links chlorin e6 (Ce6) and doxorubicin (DOX) with hyaluronic acid through a glutathione (GSH)-sensitive disulfide bond, resulting their fluorescence quenching. Notably, their fluorescence and cytotoxicity are specifically activated in tumor cells, not normal ones, due to the endogenous GSH-mediated cleavage of disulfide bonds. Furthermore, PDT is activated in tumor cells with 660 nm laser, and GSH consumption reshapes redox homeostasis balance, thereby synergistically enhancing the anti-tumor efficacy with chemotherapy. HCCD predominantly accumulates in tumors in vivo, enabling precise localization and guidance for PDT and chemotherapy. This approach results in a significant reduction in tumor size, by a factor of 11 compared to the control group, with tumors nearly disappearing. Additionally, HCCD with the toll-like receptor 7 agonist imiquimod (R837) and anti-programmed death ligand 1 (anti-PD-L1) activated systemic immune response, suppressing distant tumor growth. Therefore, it's a promising strategy for precise tumor targeting and combination therapy, with potential in immunotherapy to inhibit primary and metastatic tumor growth.
肿瘤微环境给活性氧治疗带来了重大挑战，并且无法长时间保留小分子药物，导致治疗效果不佳。在此，开发了一种基于透明质酸的纳米平台（HCCD）用于联合化疗和光动力疗法（PDT）。该纳米平台通过谷胱甘肽（GSH）敏感的二硫键将氯e6（Ce6）和阿霉素（DOX）与透明质酸连接起来，导致它们的荧光猝灭。值得注意的是，由于内源性GSH介导的二硫键断裂，它们的荧光和细胞毒性在肿瘤细胞而非正常细胞中被特异性激活。此外，用660nm激光在肿瘤细胞中激活PDT，GSH消耗重塑氧化还原稳态平衡，从而与化疗协同增强抗肿瘤疗效。HCCD在体内主要积聚在肿瘤中，为PDT和化疗实现精确的定位和引导。与对照组相比，这种方法使肿瘤大小显著缩小，缩小了11倍，肿瘤几乎消失。此外，带有Toll样受体7激动剂咪喹莫特（R837）和抗程序性死亡配体1（抗PD-L1）的HCCD激活了全身免疫反应，抑制远处肿瘤生长。因此，这是一种用于精确肿瘤靶向和联合治疗的有前景的策略，在免疫治疗中具有抑制原发性和转移性肿瘤生长的潜力。
