Sun Xiaoxiao, Liang Xiaoye, Wang YuKai, Ma Pengcheng, Xiong Weiwei, Qian Shiyu, Cui Yu, Zhang Haiyang, Chen Xiang, Tian Fang, Shi Yang, Zheng Fenfen, Li Lingling
Department of Pharmaceutics, School of Pharmacy, Nanjing Medical University, Nanjing, 211166, China.
School of Environmental & Chemical Engineering, Jiangsu University of Science and Technology, Zhenjiang, 212003, China.
Biomaterials. 2023 Oct;301:122263. doi: 10.1016/j.biomaterials.2023.122263. Epub 2023 Jul 31.
The in-situ generation of therapeutic agents in targeted lesions is promising for revolutionizing oncotherapy but is limited by the low production efficiency. Given the specific tumor microenvironment (TME) of colorectal cancer (CRC), i.e., mild acidity, overexpressed HO, glutathione (GSH) and HS, we develop phycocyanin (PC) encapsulated PZTC/SS/HA nanocapsules (NCs) for TME-responsive, protein-assisted "turn-on'' therapy of CRC. The NCs are prepared by sequentially assembling Cu-tannic acid (TA) coordination shell, disulfide bond-bearing cross-linker, and hyaluronic acid (HA) on the sacrificial template ZIF-8, thus achieving pH-, GSH-responsiveness, and tumor targeting capability, respectively. Once reaching the CRC sites, the NCs can quickly disintegrate and release Cu and PC, accompanied by subsequent endogenous HS-triggered generation of copper sulfide (CuS). Significantly, the intracellular sulfidation process can be accelerated by PC, thereby enabling efficient photothermal therapy (PTT) under NIR-Ⅱ laser. Besides, Cu-associated chemodynamic therapy (CDT) can be simultaneously activated and enhanced by PTT-induced local hyperthermia and disulfide bond-induced GSH consumption. This CRC-targeted and TME-activated synergistic PTT/CDT strategy displays high therapeutic efficacy both in vitro and in vivo, which can open up a new avenue for biomolecule-assisted in-situ nanoagent generation and effective TME-responsive synergistic treatment of CRC.
在靶向病灶中原位生成治疗剂有望彻底改变肿瘤治疗方法，但受限于低生产效率。鉴于结直肠癌（CRC）特定的肿瘤微环境（TME），即轻度酸性、高表达的血红素氧合酶（HO）、谷胱甘肽（GSH）和硫化氢（HS），我们开发了藻蓝蛋白（PC）包裹的PZTC/SS/HA纳米胶囊（NCs），用于对TME有响应的、蛋白质辅助的CRC“开启”治疗。通过在牺牲模板ZIF-8上依次组装铜-单宁酸（TA）配位壳、含二硫键的交联剂和透明质酸（HA）来制备NCs，从而分别实现pH响应性、GSH响应性和肿瘤靶向能力。一旦到达CRC部位，NCs可迅速分解并释放铜和PC，随后内源性HS引发硫化铜（CuS）的生成。值得注意的是，PC可加速细胞内硫化过程，从而在近红外二区（NIR-Ⅱ）激光照射下实现高效光热疗法（PTT）。此外，PTT诱导的局部热疗和二硫键诱导的GSH消耗可同时激活并增强与铜相关的化学动力学疗法（CDT）。这种针对CRC且由TME激活的协同PTT/CDT策略在体外和体内均显示出高治疗效果，可为生物分子辅助原位纳米制剂生成以及有效的TME响应性CRC协同治疗开辟新途径。
