Abstract：
Colorectal cancer (CRC) is a major global health concern, and the development of effective treatment strategies is crucial. Enzyme prodrug therapy (EPT) shows promise in combating tumors but faces challenges in achieving sustained expression of therapeutic enzymes and optimal biological distribution. To address these issues, a fungi-triggered in situ chemotherapeutics generator (named as SC@CS@5-FC) was constructed via oral delivery of a prodrug (5-fluorocytosine, 5-FC) for the treatment of orthotopic colorectal tumor. When SC@CS@5-FC targets the tumor through tropism by Saccharomyces cerevisiae (SC), the chemotherapeutic generator could be degraded under abundant hyaluronidase (HAase) in the tumor microenvironment by an enzyme-responsive gate to release prodrug (5-FC). And nontoxic 5-FC was catalyzed to toxic chemotherapy drug 5-fluorouracil (5-FU) by cytosine deaminase (CD) of SC. Meanwhile, SC and zinc-coordinated chitosan nanoparticles could be used as immune adjuvants to activate antigen-presenting cells and further enhance the therapeutic effect. Our results demonstrated that SC@CS@5-FC could effectively inhibit tumor growth and prolong mouse survival in an orthotopic colorectal cancer model. This work utilizes living SC as a dynamotor and positioning system for the chemotherapeutic generator SC@CS@5-FC, providing a strategy for oral enzyme prodrug therapy for the treatment of orthotopic colorectal.
摘要：
结直肠癌（CRC）是全球主要的健康问题，制定有效的治疗策略至关重要。酶前药疗法（EPT）在对抗肿瘤方面显示出希望，但在实现治疗性酶的持续表达和最佳生物分布方面面临挑战。为了解决这些问题,通过口服前药（5-氟胞嘧啶，5-FC）用于治疗原位结直肠肿瘤。当SC@CS@5-FC通过酿酒酵母（SC）的嗜性靶向肿瘤时，在肿瘤微环境中丰富的透明质酸酶（HAase）下，通过酶响应性门释放前药（5-FC）可以降解化疗剂。无毒的5-FC被SC的胞嘧啶脱氨酶（CD）催化成毒性化疗药物5-氟尿嘧啶（5-FU）。同时,SC和锌配位壳聚糖纳米粒可以作为免疫佐剂，激活抗原呈递细胞，进一步提高治疗效果。我们的结果表明，在原位结直肠癌模型中，SC@CS@5-FC可以有效抑制肿瘤生长并延长小鼠生存期。这项工作利用生活SC作为化疗发生器SC@CS@5-FC的发电机和定位系统，为原位结直肠的口服酶前药治疗提供策略。
