Abstract

Colorectal cancer (CRC), is the second cause of cancer-related deaths worldwide is one of the most prevalent types of cancers. Conventional treatment continues to rely on surgery, chemotherapy, and radiotherapy, but for advanced cases, adjuvant chemotherapy remains the main approach for improving surgical outcomes and lower the disease recurrence probability. Chemotherapy-induced gastrointestinal (GI) toxicity is the main dose-limiting factor for many chemotherapeutic regimens, including 5-FU, and one of the biggest oncological challenges. Up to 40% of the patients receiving 5-FU get mucositis, 10–15% of which develop severe symptoms. In this context, our study aimed to develop a bioinspired nanosized drug delivery system as a strategy to reduce 5-FU associated side effects, such as GI mucositis. To this end, SF-based nanoparticles were prepared and characterized in terms of size and morphology, as well as in terms of in vitro antitumoral activity on a biomimetic colorectal cancer model by investigation of apoptosis, DNA fragmentation, and release of reactive oxygen species. Additionally, the capacity of the SF-based nanocarriers to offer intestinal protection against 5-FU-induced GI mucositis was evaluated in vivo using a mouse model that mimics the chemotherapy-associated gut mucositis occurring in colorectal cancer. Our studies show that silk fibroin nanoparticles efficiently deliver 5-FU to tumor cells in vitro while protecting against drug-induced GI mucositis in a mouse model.

摘要

结直肠癌 (CRC) 是全球癌症相关死亡的第二大原因，也是最普遍的癌症类型之一。常规治疗继续依赖手术、化疗和放疗，但对于晚期病例，辅助化疗仍是改善手术效果和降低疾病复发概率的主要方法。化疗引起的胃肠 (GI) 毒性是许多化疗方案（包括 5-FU）的主要剂量限制因素，也是最大的肿瘤学挑战之一。多达 40% 的接受 5-FU 治疗的患者会患上粘膜炎，其中 10-15% 会出现严重的症状。在这种情况下，我们的研究旨在开发一种仿生纳米级药物递送系统，作为减少 5-FU 相关副作用（如胃肠道粘膜炎）的策略。为此，通过研究细胞凋亡、DNA 断裂和活性氧的释放，对仿生结直肠癌模型的体外抗肿瘤活性。此外，使用模拟结直肠癌中发生的与化疗相关的肠道黏膜炎的小鼠模型，在体内评估了基于 SF 的纳米载体对 5-FU 诱导的胃肠黏膜炎提供肠道保护的能力。我们的研究表明，丝素蛋白纳米颗粒在体外有效地将 5-FU 递送至肿瘤细胞，同时在小鼠模型中防止药物诱导的胃肠道粘膜炎。