Abstract:
Temozolomide (TMZ) is an oral DNA-alkylating drug used in colorectal cancer (CRC) chemotherapy. In this work, we proposed a safe and biomimetic platform for macrophages-targeted delivery of TMZ and O6-benzylguanine (O6-BG). TMZ was loaded in poly (D, l-lactide-coglycolide) (PLGA) nanoparticles, followed by sequential coating with O6-BG-grafted chitosan (BG-CS) layers and yeast shell walls (YSW) via layer-by-layer assembly (LBL) process, forming TMZ@P-BG/YSW biohybrids. Due to the yeast cell membrane-camouflage, TMZ@P-BG/YSW particles exhibited significantly enhanced colloidal stability as well as low premature drug leakage in simulated gastrointestinal conditions. In vitro drug release profiles of TMZ@P-BG/YSW particles revealed noticeable higher TMZ release in simulated tumor acidic environment within 72 h. Meanwhile, O6-BG could down-regulate MGMT expression in CT26 colon carcinoma cells, ultimately facilitating TMZ-induced tumor cell death. After oral delivery of yeast cell membrane-camouflaged particles containing fluorescent tracer (Cy5), TMZ@P-BG/YSW and bare YSW displayed high retention time of 12 h in the colon and small intestine (ileum). Correspondingly, oral gavage administration of TMZ@P-BG/YSW particles afforded favorable tumor-specific retention and superior tumor growth inhibition. Overall, TMZ@P-BG/YSW is validated to be a safe, targetable and effective formulation, paving a new avenue towards highly effective and precise treatment of malignancies.
摘要:
替莫唑胺(TMZ)是一种用于结直肠癌(CRC)化疗的口服DNA烷基化药物。在这项工作中,我们提出了一个安全的仿生平台,用于巨噬细胞靶向递送TMZ和O6-苄基鸟嘌呤(O6-BG)。TMZ加载在聚(D,l-丙交酯-共乙交酯)(PLGA)纳米颗粒,然后通过逐层组装(LBL)过程依次涂覆O6-BG接枝的壳聚糖(BG-CS)层和酵母壳壁(YSW),形成TMZ@P-BG/YSW生物杂种。由于酵母细胞膜伪装,TMZ@P-BG/YSW颗粒在模拟胃肠道条件下表现出显着增强的胶体稳定性以及低的过早药物泄漏。TMZ@P-BG/YSW颗粒的体外药物释放曲线显示,在模拟肿瘤酸性环境中,在72h内TMZ释放明显更高。O6-BG可以下调CT26结肠癌细胞MGMT的表达,最终促进TMZ诱导的肿瘤细胞死亡。口服含有荧光示踪剂(Cy5)的酵母细胞膜伪装颗粒后,TMZ@P-BG/YSW和裸YSW在结肠和小肠(回肠)中显示出12小时的高保留时间。相应地,经口灌胃给予TMZ@P-BG/YSW颗粒可提供良好的肿瘤特异性滞留和优异的肿瘤生长抑制作用.总的来说,TMZ@P-BG/YSW被验证为安全的,有针对性和有效的配方,为高效和精确治疗恶性肿瘤开辟了一条新途径。