Zhang Huijuan, Wang Yaping, Li Mengting, Cao Kexuan, Qi Zijun, Zhu Ling, Zhang Zhenzhong, Hou Lin
School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China.
Key Laboratory of Targeting Therapy and Diagnosis for Critical Diseases, Zhengzhou 450000, China.
Asian J Pharm Sci. 2022 Nov;17(6):892-907. doi: 10.1016/j.ajps.2022.09.003. Epub 2022 Oct 19.
Colorectal cancer is often accompanied by multiple organ metastasis. Anaerobic (BI) bacterial can selectively grow in hypoxic colorectal tumor microenvironment (TME), to own the natural advantage of preferentially colorectal tumor targeting. Herein, a self-guidance biological hybrid drug delivery system (BI-ES-FeAlg/DOX) based on BI was constructed to inhibit the proliferation and metastasis of colon cancer. Results demonstrated that BI-ES-FeAlg/DOX could overcome physical barriers to target and accumulate in colon tumor tissues. Then DOX was released to kill tumor cells along with the phase transition (solid to liquid) of FeAlg hydrogel, due to Fe was reduced to Feby intracellular GSH. Meanwhile, BI-ES selectively colonized into tumors and expressed endostatin (ES) protein to down-regulate VEGF and bFGF expression, exerting anti-angiogenic effect. Moreover, FeAlg catalyzed HO in the local tumor to generate cytotoxic ·OH, further enhancing the antitumor effect. The pharmacodynamic result in AOM/DSS model proved that BI-ES-FeAlg/DOX had the best therapeutic effect, with the final V/V of 2.19 ± 0.57, which was significantly lower than the other groups. Meanwhile, on CT-26 tumor-bearing model, it also showed an outstanding anti-tumor effect with inhibition rate of 82.12% ± 3.08%. In addition, lung metastases decreased significantly in tumor metastasis model after BI-ES-FeAlg/DOX treatment.
结直肠癌常伴有多器官转移。厌氧（BI）细菌能够在缺氧的结直肠癌肿瘤微环境（TME）中选择性生长，具有优先靶向结直肠癌肿瘤的天然优势。在此，构建了一种基于BI的自引导生物杂化药物递送系统（BI-ES-FeAlg/DOX），以抑制结肠癌的增殖和转移。结果表明，BI-ES-FeAlg/DOX能够克服物理屏障，靶向并积聚在结肠肿瘤组织中。然后，由于细胞内谷胱甘肽（GSH）将Fe还原为Fe，DOX随着FeAlg水凝胶的相转变（从固体到液体）而释放，从而杀死肿瘤细胞。同时，BI-ES选择性地在肿瘤中定殖并表达内皮抑素（ES）蛋白，以下调血管内皮生长因子（VEGF）和碱性成纤维细胞生长因子（bFGF）的表达，发挥抗血管生成作用。此外，FeAlg催化局部肿瘤中的H₂O₂生成具有细胞毒性的·OH，进一步增强抗肿瘤效果。在AOM/DSS模型中的药效学结果证明，BI-ES-FeAlg/DOX具有最佳治疗效果，最终肿瘤体积与初始肿瘤体积之比（V/V）为2.19±0.57，显著低于其他组。同时，在CT-26荷瘤模型上，它也表现出出色的抗肿瘤效果，抑制率为82.12%±3.08%。此外，在BI-ES-FeAlg/DOX治疗后的肿瘤转移模型中，肺转移明显减少。
