ABSTRACT

Gefitinib (GEB) is one of the drugs used for patients with epidermal growth factor receptor (EGFR)-positive mutations in non-small cell lung cancer (NSCLC). However, application of GEB is limited by its low water solubility, stability, and utilization rate, especially the side effects while GEB is given by oral. In this study, nanoliposome was used as a carrier to prepare nanoliposome compound drug (GL) by embedding GEB in the nanoliposome perfectly combined with green nontoxic solvent and thin-film dispersion method. The nanoliposome structure was expected to improve the water solubility and biocompatibility of GEB, thus improving the effect of cancer treatment. The surface electronegative nanoliposomes can effectively avoid protein adsorption and prolong the circulation time in vivo. Meanwhile, the ratio of lecithin to cholesterol (LE/CH) was explored to maximize the encapsulation efficiency of nanoliposome. Subsequent test results showed that GL exhibited better stability, smaller particle size and higher encapsulation efficiency. In addition, in vitro drug release curve also further confirmed that GL had a promising drug sustained-release effect. In particular, a series of in vitro tests such as cell activity, apoptosis, colony formation, scratch, invasion, and cell cycle assays were performed. The results indicated that GL significantly enhanced the pro-apoptotic effect on A549 cells. Most cell cycles of A549 cells were blocked in the G0/G1 phase influenced by GL, thus inhibiting the proliferation of cancer cells. In vivo anti-tumor studies showed that compared with pure GEB, GL had a significant inhibiting effect on NSCLC. In conclusion, the GL which was synthesized by a simple method in this study significantly improved the treatment effect of cancer cells, which proved that the nanoliposome carrier had an excellent application prospect in the treatment of lung cancer.

摘要

吉非替尼（GEB）是用于非小细胞肺癌（NSCLC）表皮生长因子受体（EGFR）阳性突变患者的药物之一。然而，GEB的应用受到其水溶性低、稳定性和利用率低的限制，尤其是GEB口服给药的副作用。本研究以纳米脂质体为载体，将GEB嵌入纳米脂质体中，结合绿色无毒溶剂和薄膜分散法，制备纳米脂质体复合药物（GL）。纳米脂质体结构有望提高GEB的水溶性和生物相容性，从而提高癌症治疗效果。表面带负电的纳米脂质体可有效避免蛋白质吸附，延长体内循环时间. 同时，探索了卵磷脂与胆固醇的比率（LE/CH）以最大化纳米脂质体的包封效率。随后的测试结果表明，GL表现出更好的稳定性、更小的粒径和更高的包封效率。此外，体外药物释放曲线也进一步证实了GL具有良好的药物缓释作用。特别是进行了细胞活性、细胞凋亡、集落形成、划痕、侵袭和细胞周期测定等一系列体外测试。结果表明GL显着增强了对A549细胞的促凋亡作用。受GL影响，A549细胞的大部分细胞周期在G0/G1期被阻断，从而抑制癌细胞的增殖。体内抗肿瘤研究表明，与纯GEB相比，GL对NSCLC有显着的抑制作用。综上所述，本研究通过简单方法合成的GL显着提高了对癌细胞的治疗效果，证明纳米脂质体载体在肺癌治疗中具有良好的应用前景。