Department and Institute of Pharmacology, National Yang-Ming University, Taipei, 112, Taiwan.
Department of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, Taipei, 112, Taiwan.
Small. 2019 Dec;15(49):e1903296. doi: 10.1002/smll.201903296. Epub 2019 Nov 11.
Irinotecan is one of the main chemotherapeutic agents for colorectal cancer (CRC). MicroRNA-200 (miR-200) has been reported to inhibit metastasis in cancer cells. Herein, pH-sensitive and peptide-modified liposomes and solid lipid nanoparticles (SLN) are designed for encapsulation of irinotecan and miR-200, respectively. These peptides include one cell-penetrating peptide, one ligand targeted to tumor neovasculature undergoing angiogenesis, and one mitochondria-targeting peptide. The peptide-modified nanoparticles are further coated with a pH-sensitive PEG-lipid derivative with an imine bond. These specially-designed nanoparticles exhibit pH-responsive release, internalization, and intracellular distribution in acidic pH of colon cancer HCT116 cells. These nanoparticles display low toxicity to blood and noncancerous intestinal cells. Delivery of miR-200 by SLN further increases the cytotoxicity of irinotecan-loaded liposomes against CRC cells by triggering apoptosis and suppressing RAS/β-catenin/ZEB/multiple drug resistance (MDR) pathways. Using CRC-bearing mice, the in vivo results further indicate that irinotecan and miR-200 in pH-responsive targeting nanoparticles exhibit positive therapeutic outcomes by inhibiting colorectal tumor growth and reducing systemic toxicity. Overall, successful delivery of miR and chemotherapy by multifunctional nanoparticles may modulate β-catenin/MDR/apoptosis/metastasis signaling pathways and induce programmed cancer cell death. Thus, these pH-responsive targeting nanoparticles may provide a potential regimen for effective treatment of colorectal cancer.
伊立替康是结直肠癌（CRC）的主要化疗药物之一。有报道称 microRNA-200（miR-200）可抑制癌细胞的转移。本文设计了 pH 敏感型和肽修饰的脂质体和固体脂质纳米粒（SLN）分别包封伊立替康和 miR-200。这些肽包括一个细胞穿透肽、一个靶向肿瘤新生血管形成的血管生成的配体和一个靶向线粒体的肽。肽修饰的纳米粒进一步用具有亚胺键的 pH 敏感的 PEG-脂质衍生物进行涂层。这些专门设计的纳米粒在酸性 pH 值的结肠癌细胞 HCT116 中表现出 pH 响应性释放、内化和细胞内分布。这些纳米粒对血液和非癌性肠细胞的毒性较低。SLN 递送 miR-200 进一步通过触发细胞凋亡和抑制 RAS/β-catenin/ZEB/多药耐药（MDR）途径增加载 miR-200 的脂质体对 CRC 细胞的细胞毒性。使用结直肠癌荷瘤小鼠，体内结果进一步表明，pH 响应性靶向纳米粒中的伊立替康和 miR-200 通过抑制结直肠肿瘤生长和降低全身毒性表现出积极的治疗效果。总之，多功能纳米粒成功递送 miR 和化疗药物可能调节β-catenin/MDR/凋亡/转移信号通路并诱导程序性癌细胞死亡。因此，这些 pH 响应性靶向纳米粒可能为结直肠癌的有效治疗提供一种有潜力的方案。
