BACKGROUND The emergence of resistance to chemotherapy or target therapy, tumor metastasis, and systemic toxicity caused by available anticancer drugs hamper the successful colorectal cancer (CRC) treatment. The rise in epidermal growth factor receptor (EGFR; human epidermal growth factor receptor 1; HER1) expression and enhanced phosphorylation of HER2 and HER3 are associated with tumor resistance, metastasis and invasion, thus resulting in poor outcome of anti-CRC therapy. The use of afatinib, a pan-HER inhibitor, is a potential therapeutic approach for resistant CRC. Additionally, miR-139 has been reported to be negatively correlated with chemoresistance, metastasis, and epithelial-mesenchymal transition (EMT) of CRC. Hence, we develop a nanoparticle formulation consisting of a polymer core to carry afatinib or miR-139, which is surrounded by lipids modified with a targeting ligand and a pH-sensitive penetrating peptide to improve the anticancer effect of cargos against CRC cells. RESULTS Our findings show that this formulation displays a spherical shape with core/shell structure, homogeneous particle size distribution and negative zeta potential. The prepared formulations demonstrate a pH-sensitive release profile and an enhanced uptake of cargos into human colorectal adenocarcinoma Caco-2 cells in response to the acidic pH. This nanoparticle formulation incorporating afatinib and miR-139 exhibits low toxicity to normal cells but shows a better inhibitory effect on Caco-2 cells than other formulations. Moreover, the encapsulation of afatinib and miR-139 in peptide-modified nanoparticles remarkably induces apoptosis and inhibits migration and resistance of Caco-2 cells via suppression of pan-HER tyrosine kinase/multidrug resistance/metastasis pathways. CONCLUSION This study proposes a multifunctional nanoparticle formulation for targeted modulation of apoptosis/EGFR/HER/EMT/resistance/progression pathways to increase the sensitivity of colon cancer cells to afatinib.

中文翻译：

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通过使用与双重pH响应肽和靶向肽缀合的脂质聚合物纳米颗粒，改善afatinib和microRNA的抗癌作用。

背景技术由可用抗癌药引起的对化学疗法或靶标疗法的抗性，肿瘤转移和全身毒性的出现阻碍了成功的结直肠癌（CRC）治疗。表皮生长因子受体（EGFR;人表皮生长因子受体1; HER1）表达的升高以及HER2和HER3磷酸化的增强与肿瘤抵抗，转移和侵袭有关，因此导致抗CRC治疗的结果差。泛HER抑制剂阿法替尼的使用是抗药性CRC的潜在治疗方法。此外，据报道，miR-139与CRC的化学耐药性，转移和上皮间质转化（EMT）呈负相关。因此，我们开发了一种由聚合物核组成的纳米粒子制剂，可携带afatinib或miR-139，它被靶向配体和pH敏感的穿透肽修饰的脂质包围，从而改善了货物对CRC细胞的抗癌作用。结果我们的发现表明该制剂显示出具有核/壳结构，均匀的粒度分布和负的ζ电势的球形。所制备的制剂表现出pH敏感的释放曲线，并且响应于酸性pH，增加了货物被吸收到人结肠直肠腺癌Caco-2细胞中的能力。掺入阿法替尼和miR-139的纳米颗粒制剂对正常细胞毒性低，但对Caco-2细胞的抑制作用优于其他制剂。而且，afatinib和miR-139在肽修饰的纳米粒子中的封装可通过抑制pan-HER酪氨酸激酶/多药耐药性/转移途径显着诱导凋亡，并抑制Caco-2细胞的迁移和耐药性。结论这项研究提出了一种多功能的纳米颗粒制剂，用于靶向调节细胞凋亡/ EGFR / HER / EMT /耐药/进展途径，以提高结肠癌细胞对阿法替尼的敏感性。