Cheng Yinjia, Liu Qiangyu, Wang Yuqing, Liu Muhai, Mo Qin, Zeng Fangyu, Li Yuting, Liu Wenlong, Qin Siyong, Ma Yihan, Zhang Aiqing, Zhang Xianzheng
Key Laboratory of Catalysis and Energy Materials Chemistry of Ministry of Education & Hubei Key Laboratory of Catalysis and Materials Science, School of Chemistry and Materials Science, South-Central Minzu University, Wuhan 430074, China.
Key Laboratory of Catalysis and Energy Materials Chemistry of Ministry of Education & Hubei Key Laboratory of Catalysis and Materials Science, School of Chemistry and Materials Science, South-Central Minzu University, Wuhan 430074, China.
J Colloid Interface Sci. 2025 Oct 15;696:137854. doi: 10.1016/j.jcis.2025.137854. Epub 2025 May 10.
The reactive oxygen species (ROS)-based chemodynamic therapy (CDT) and sonodynamic therapy (SDT) have garnered significant interests in advanced tumor treatments. However, their therapeutic efficacy is severely hindered by tumor hypoxia and overexpressed antioxidant glutathione (GSH) in the tumor microenvironment (TME). Motivated by the concept of metal coordination-based nanomedicine, we proposed an innovative strategy for synergistic tumor therapy tailored to the TME. Herein, we developed a multifunctional targeted delivery nanosystem based on the tirapazamine (TPZ)-loaded BT@M/T@T(Cu)GH cascade nanoreactor to enhance the synergistic efficacy of CDT, SDT, chemotherapy (CT) and starvation therapy (ST) against breast cancer. The rationally designed nanoreactor was constructed through covalent conjugation of glucose oxidase (GOx) onto TPZ-loaded BT@M/T@T(Cu) nanoparticles, wherein the formed tannic acid/copper (Ⅱ) (T(Cu)) network served as the "nanovalve"for BT@M/T nanoparticles. Surface functionalization with hyaluronic acid (HA) enabled BT@M/T@T(Cu) nanoparticles to effectively target CD44-overexpressed 4T1 breast tumors via passive targeting and active targeting effect, while mitigating cytotoxicity toward normal cells/tissues. Following successful tumor accumulation, BT@M/T@T(Cu)GH nanoparticles underwent pH-dependent disassembly and released TPZ, Cu and GOx, initiating a cascade of integrated therapeutic functions, including redox balance disruption, starvation, oxidative cytotoxicity, and hypoxia-activated chemotoxicity. When exposed to ultrasound (US) irradiation, BT@M/T@T(Cu)GH nanoparticles demonstrated sonosensitization capability, generating substantial singlet oxygen (O) through energy transfer processes. Owing to all these prominent features, the all-in-one nanomedicine exhibited significant apoptotic cell death and noteworthy tumor eradication in vivo, via synergistic combination of GOx-based ST, self-amplified CDT, hypoxia-activated CT, and US-activated SDT. Additionally, the administration of BT@M/T@T(Cu)GH had negligible effects on the normal growth. Taken together, this work establishes a versatile TiO-based nanosystem integrating tumor targeting and multi-mode synergistic therapy of breast cancer, offering a novel strategy for highly effective and precise treatment of malignancies.
基于活性氧（ROS）的化学动力学疗法（CDT）和声动力疗法（SDT）在晚期肿瘤治疗中引起了广泛关注。然而，肿瘤微环境（TME）中的肿瘤缺氧和过表达的抗氧化剂谷胱甘肽（GSH）严重阻碍了它们的治疗效果。受基于金属配位的纳米医学概念的启发，我们提出了一种针对TME量身定制的协同肿瘤治疗创新策略。在此，我们开发了一种基于负载替拉帕米（TPZ）的BT@M/T@T（Cu）GH级联纳米反应器的多功能靶向递送纳米系统，以增强CDT、SDT、化疗（CT）和饥饿疗法（ST）对乳腺癌的协同疗效。通过将葡萄糖氧化酶（GOx）共价偶联到负载TPZ的BT@M/T@T（Cu）纳米颗粒上构建了合理设计的纳米反应器，其中形成的单宁酸/铜（Ⅱ）（T（Cu））网络充当BT@M/T纳米颗粒的“纳米阀”。用透明质酸（HA）进行表面功能化使BT@M/T@T（Cu）纳米颗粒能够通过被动靶向和主动靶向作用有效靶向CD44过表达的4T1乳腺肿瘤，同时减轻对正常细胞/组织的细胞毒性。在成功的肿瘤积累后，BT@M/T@T（Cu）GH纳米颗粒经历pH依赖性分解并释放TPZ、铜和GOx，引发一系列综合治疗功能，包括氧化还原平衡破坏、饥饿、氧化细胞毒性和缺氧激活的化学毒性。当暴露于超声（US）照射时，BT@M/T@T（Cu）GH纳米颗粒表现出声敏化能力，通过能量转移过程产生大量单线态氧（O）。由于所有这些突出特性，这种一体化纳米药物通过基于GOx的ST、自增强CDT、缺氧激活的CT和US激活的SDT的协同组合，在体内表现出显著的凋亡细胞死亡和值得注意的肿瘤根除效果。此外，BT@M/T@T（Cu）GH的给药对正常生长的影响可忽略不计。综上所述，这项工作建立了一种多功能的基于TiO的纳米系统，整合了肿瘤靶向和乳腺癌的多模式协同治疗，为高效精确治疗恶性肿瘤提供了一种新策略。
