Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, P. R. China.
Biomater Sci. 2021 Mar 10;9(5):1855-1871. doi: 10.1039/d0bm01950j.
The satisfactory efficient tumor treatment and complete tumor ablation using a mono-therapeutic approach are limited owing to the tumor complexity, diversity, heterogeneity and the multiple pathways involved in tumor pathogenesis. Herein, novel, intelligent and tumor microenvironment (TME)-responsive biotin/R8 peptide co-modified nanocarriers (BRNC) loading paclitaxel (PTX)/glucose oxidase (GOx) were constructed. GOx could catalyze the oxidation of intracellular glucose to gluconic acid and poisonous H2O2 to cause the deterioration of the tumor survival microenvironment, simultaneously achieving starvation and oxidation therapy. The acidic amplification during the GOx-mediated oxidation progress could in turn accelerate the cleavage of the acid-degradable hydrazone bond, promoting the deep penetration of nanocarriers into tumors. Even better, the aforementioned two aspects further increased the tumors' sensitivity to chemotherapeutic agents. Both in vitro and in vivo investigations indicated that the co-administration of GOx-BRNC and PTX-BRNC can remarkably improve the therapeutic efficacy and reduce side effects through the high-specific tumor targeting multimodal synergistic starvation/oxidation/chemotherapy, which would be a promising strategy for the next generation cancer therapy.
由于肿瘤的复杂性、多样性、异质性以及肿瘤发病机制中涉及的多种途径，单一治疗方法很难达到令人满意的肿瘤治疗效果和完全消融肿瘤。在此，我们构建了一种新型的、智能的、肿瘤微环境（TME）响应性生物素/R8 肽共修饰纳米载体（BRNC），负载紫杉醇（PTX）/葡萄糖氧化酶（GOx）。GOx 可以催化细胞内葡萄糖氧化为葡萄糖酸和有毒的 H2O2，导致肿瘤生存微环境恶化，同时实现饥饿和氧化治疗。在 GOx 介导的氧化过程中的酸性扩增反过来又可以加速酸降解腙键的裂解，促进纳米载体更深地渗透到肿瘤中。更好的是，上述两个方面进一步提高了肿瘤对化疗药物的敏感性。体外和体内研究均表明，通过高特异性肿瘤靶向多模式协同饥饿/氧化/化疗联合应用 GOx-BRNC 和 PTX-BRNC，可显著提高治疗效果，降低副作用，这将是下一代癌症治疗的一种有前途的策略。
