Wang Yuhan, Xie Limin, Li Xinxin, Wang Ling, Yang Zhimou
Tianjin Key Laboratory of Inflammation Biology, Department of Pharmacology, School of Basic Medicine, Tianjin Medical University, Tianjin, 300070, PR China.
Key Laboratory of Bioactive Materials, Ministry of Education, State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Collaborative Innovation Center of Chemical Science and Engineering, National Institute of Functional Materials, Nankai University, Tianjin, 300071, PR China.
Bioact Mater. 2023 Sep 16;31:549-562. doi: 10.1016/j.bioactmat.2023.09.006. eCollection 2024 Jan.
Herein, we designed to simultaneously respond to two enzymes: alkaline phosphatase and matrix metalloproteinase 2, which is commonly found in highly malignant cancer cell lines containing B16-F10 murine melanoma cells and CT26 murine colon carcinoma cells. We used the regional differences in the expression levels of dual-markers to accurately release immune molecule IND into tumor microenvironment for the activation of anti-tumor related immune effects, while self-assembly occurs. The dual-enzyme response process can further regulate the peptide precursors' self-assembly in the form of short rod-shaped nanofibers, enabling the delivery of the loaded chemotherapeutic drug HCPT into the cancer cells and further allowing the peptide assemblies to escape from lysosomes and return to cytoplasm in the form of tiny nanoparticles to induce apoptosis of cancer cells. This process does not occur in the single-positive breast cancer cell line MCF-7 or the normal hepatocytes cell line LO2, indicating the selectivity of the cancer cells exhibited using our strategy. studies revealed that can effectively cooperate with chemotherapy to enhance the immunotherapy effect and induce immune responses associated with elevated pro-inflammatory cytokines to inhibit malignant tumors growth. Our dual-enzyme responsive chemo-immunotherapy strategy feasible in anti-tumor treatment, provides a new avenue for regulating peptide self-assembly to adapt to diverse tumor properties and may eventually be used for the development of novel multifunctional anti-tumor nanomedicines.
在此，我们设计了一种能同时响应两种酶的体系：碱性磷酸酶和基质金属蛋白酶2，这两种酶常见于含有B16-F10小鼠黑色素瘤细胞和CT26小鼠结肠癌细胞的高恶性癌细胞系中。我们利用双标记物表达水平的区域差异，在自组装发生的同时，将免疫分子IND准确释放到肿瘤微环境中，以激活抗肿瘤相关免疫效应。双酶响应过程可以进一步以短棒状纳米纤维的形式调节肽前体的自组装，使负载的化疗药物喜树碱（HCPT）递送至癌细胞中，并进一步使肽组装体以微小纳米颗粒的形式从溶酶体中逃逸并返回细胞质，从而诱导癌细胞凋亡。此过程在单阳性乳腺癌细胞系MCF-7或正常肝细胞系LO2中不会发生，这表明我们的策略所展现出的对癌细胞的选择性。研究表明，其能够有效地与化疗协同作用，增强免疫治疗效果，并诱导与促炎细胞因子升高相关的免疫反应，以抑制恶性肿瘤生长。我们的双酶响应化学免疫治疗策略在抗肿瘤治疗中是可行的，为调节肽自组装以适应不同肿瘤特性提供了一条新途径，并最终可能用于开发新型多功能抗肿瘤纳米药物。
