Department of Otolaryngology Head and Neck Surgery, Sir Mortimer B. Davis-Jewish General Hospital, McGill University, Montreal, QC, Canada; Segal Cancer Centre and Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, Departments of Medicine, Oncology, and Pharmacology and Therapeutics, Faculty of Medicine, McGill University, Montreal, QC, Canada; Department of Oral Pathology, Faculty of Dentistry, Federal University of Paraiba (UFPB), Joao Pessoa, PB, Brazil.
Health Technician School, Federal University of Paraiba (UFPB), Joao Pessoa, PB, Brazil.
Int J Biochem Cell Biol. 2021 May;134:105964. doi: 10.1016/j.biocel.2021.105964. Epub 2021 Mar 2.
Head and neck squamous cell carcinoma (HNSCC), a prevalent cancer worldwide, has a high incidence of loco-regional dissemination, frequent recurrence, and lower 5-year survival rates. Current gold standard treatments for advanced HNSCC rely primarily on radiotherapy and chemotherapy but with limited efficacy and significant side effects. In this study, we characterized a novel 5-fluorouracil (5-FU) carrier composed of chitosan solution (CS) and polycaprolactone (PCL) microparticles (MPs) in HNSCC preclinical models. The designed MPs were evaluated for their size, morphology, drug entrapment efficiency (EE%) and in vitro drug release profile. The anti-cancer activity of 5-FU-loaded particles was assessed in HNSCC human cell lines (CAL27 and HSC3) and in a preclinical mouse model (AT84) utilizing cell proliferation and survival, cell motility, and autophagy endpoints. The results demonstrated a 38.57 % in 5-FU entrapment efficiency associated with reduced 5-FU in vitro release up to 96 h post-exposure. Furthermore, CS-decorated PCL MPs were able to promote a significant inhibition of cancer cell proliferation based on the metabolic and colony formation assays, in comparison to controls. In contrast, CS-decorated PCL MPs did not influence the pharmacological efficacy of 5-FU to inhibit in vitro cancer cell migration. Last, cell protein analysis revealed a significant increase of autophagy and cell death evaluated by LC3-II expression and PARP1 cleavage, respectively. In summary, these results support the potential utility of CS-decorated PCL MPs as an effective 5-FU-delivery carrier to improve HNSCC therapeutic management.
头颈部鳞状细胞癌（HNSCC）是一种全球普遍存在的癌症，具有局部扩散率高、复发频繁和 5 年生存率低的特点。目前，治疗晚期 HNSCC 的金标准主要依赖于放疗和化疗，但疗效有限，且副作用明显。在本研究中，我们在 HNSCC 临床前模型中对一种由壳聚糖溶液（CS）和聚己内酯（PCL）微球（MPs）组成的新型 5-氟尿嘧啶（5-FU）载体进行了表征。设计的 MPs 进行了粒径、形态、药物包封效率（EE%）和体外药物释放特性的评价。利用细胞增殖和存活、细胞迁移和自噬终点，在 HNSCC 人细胞系（CAL27 和 HSC3）和临床前小鼠模型（AT84）中评估了负载 5-FU 的粒子的抗癌活性。结果表明，5-FU 的包封效率为 38.57%，体外释放至 96 小时后，5-FU 释放量减少。此外，与对照组相比，CS 修饰的 PCL MPs 能够显著抑制基于代谢和集落形成测定的癌细胞增殖。相比之下，CS 修饰的 PCL MPs 并不影响 5-FU 抑制体外癌细胞迁移的药理功效。最后，细胞蛋白分析显示，自噬和细胞死亡分别通过 LC3-II 表达和 PARP1 裂解评估，明显增加。综上所述，这些结果支持 CS 修饰的 PCL MPs 作为一种有效的 5-FU 递送载体，具有改善 HNSCC 治疗管理的潜力。
