厌氧菌介导的肿瘤微环境响应型纳米粒子增强肺癌疗效  

Anaerobic Bacteria-Mediated Tumor Microenvironment-Responsive Nanoparticles Enhance the Therapeutic Efficacy of Lung Cancer

作　　者：李月 熊康 卢韵 傅少志 LI Yue;XIONG Kang;LU Yun;FU Shaozhi(Department of Oncology,The Affiliated Hospital,Southwest Medical University,Luzhou 646000,China;Nuclear Medicine and Molecular Imaging Key Laboratory of Sichuan Province,Luzhou 646000,China)

机构地区：[1]西南医科大学附属医院肿瘤科,泸州646000 [2]核医学与分子影像四川省重点实验室,泸州646000

出　　处：《西南医科大学学报》2024年第3期200-205,共6页Journal of Southwest Medical University

基　　金：四川省科技厅应用基础研究项目(2020YJ0385);西南医科大学应用基础重点项目(2021ZKZD014)。

摘　　要：目的传统化疗药物不能在肿瘤内部维持高浓度,导致肺癌临床疗效降低,毒副作用严重。本研究的目的是开发一种由厌氧菌介导的新型纳米药物提升肿瘤组织药物浓度并提高治疗效果。方法合成一种可降解聚合物并制备婴儿双歧杆菌抗体修饰的阿霉素纳米粒子(Ab-DOX-s-s-NPS),体外表征其形貌、药物释放行为和细胞摄取能力;建立A549肺癌荷瘤小鼠模型,评价该纳米粒抑制肿瘤生长的效果,并考察其毒副反应。结果透射电镜(transmission electron microscopy,TEM)图像及凝胶电泳蛋白图谱等证实Ab-DOX-s-s-NPS纳米粒子的成功制备,粒径约为85.6±1.4 nm,它能与细菌良好结合;在高谷胱甘肽(glutathione,GSH)环境中能快速释放药物并被肿瘤细胞摄取;通过预植入的双歧杆菌为靶标,该纳米粒子在荷瘤小鼠体内能主动富集到肿瘤缺氧区域,显著抑制肿瘤生长,延长小鼠生存时间;且与游离阿霉素造成的心肌纤维化相比,纳米药物组没有造成显著的心脏毒性和肝肾功能损伤。结论本研究制备的Ab-DOX-s-s-NPS纳米粒子具有还原响应性,能通过双歧杆菌的招募主动靶向富集到肿瘤组织,对肺癌移植瘤具有优异的抗肿瘤效果,有望成为治疗其他恶性实体瘤的候选药物。Objective Traditional chemotherapy drugs are unable to maintain high concentration in the tumor,which leads to the reduction of clinical efficacy of lung cancer and serious side effects.The purpose of this study is to develop a novel nanodrug mediated by anaerobic bacteria to increase the drug concentration in tumor tissue and improve the therapeutic effect.Methods A degradable poly⁃mer was synthesized and doxorubicin nanoparticles(Ab-DOX-s-NPS)modified with Bifidobacterium infantis(Bi)antibody were pre⁃pared.The morphology,drug release behavior and cell uptake were characterized in vitro.An A549 lung cancer-bearing mouse model was established to evaluate the effect of the nanoparticles on inhibiting tumor growth and to investigate their toxic and side effects.Results The transmission electron microscope(TEM)image and gel electrophoresis protein map confirmed the successful preparation of Ab-DOX-s-s-NPS nanoparticles,which could combine well with bacteria.It could rapidly release drugs and be absorbed by tumor cells in high GSH environment.With the pre-implanted bifidobacterium as the target,the nanoparticles could actively enrich to the an⁃oxic regions of tumor.It could significantly inhibit the growth of tumor and prolong the survival time of mice.Compared with the myocar⁃dial fibrosis caused by free adriamycin,the nanodrug did not cause significant cardiac toxicity and liver and kidney function damage.Conclusion The nanoparticles prepared in this study were reduction-responsive and could be actively targeted and enriched into tumor tissue through the recruitment of Bi,which had excellent anti-tumor effect on lung cancer transplanted tumor.The drug system was ex⁃pected to become a new strategy for the treatment of other malignant solid tumors.

关 键 词：婴儿双歧杆菌 肿瘤乏氧 纳米粒子 多柔比星 肺癌 

分 类 号：R73-3[医药卫生—肿瘤]