Genotoxicity and in vitro investigation of Gefitinib-loaded polycaprolactone fabricated nanoparticles for anticancer activity against NCI-H460 cell lines
Genotoxicity and in vitro investigation of Gefitinib-loaded polycaprolactone fabricated nanoparticles for anticancer activity against NCI-H460 cell lines
复制标题
DOI：
10.1080/17458080.2022.2060501
复制
发表时间：
2022-12-31
影响因子：
2.8
通讯作者：
Bhattacharya, Sankha
中科院分区：
文献类型：
--
作者：
Bhattacharya, Sankha
对于非小细胞肺癌（NSCLC）的治疗，BCS II类药物吉非替尼被广泛使用。由于生物利用度差、药物释放无法控制，吉非替尼出现了副作用。为了避免此类相关问题，我们利用 Box-Behnken 设计开发了具有三种不同 PCL 分子量（平均 Mn 类似于 10,000、Mn 类似于 45,000 和 Mn 类似于 80,000）的优化吉非替尼封装的聚己内酯 (PCL) 纳米颗粒，同时了解纳米颗粒关键工艺参数的影响。对于形态表征，使用了 SEM、TEM、AFM。采用血液相容性、血小板聚集和红细胞膜完整性测试来测试纳米颗粒的生物相容性；在这些测试中报告了优异的生物相容性。体外药物释放研究证实，吉非替尼-PCL(10,000)纳米颗粒、吉非替尼-PCL(45,000)纳米颗粒和吉非替尼-PCL80,000纳米颗粒表现出显着的初始爆发效应，后期纳米颗粒具有零级动力学。通过胞质分裂阻断微核 (CBMN) 测定评估 PCL 纳米颗粒的遗传毒性，表明 NCI-H460 细胞以及微核和核芽形成中存在 DNA 损伤。此外，还进行了活性氧研究、24 和 48 小时 MTT 细胞毒性测定、稳定性、优化荧光吉非替尼 PCL(80,000)NP 的体外细胞摄取以及细胞凋亡研究。因此，研究稳定的载有吉非替尼的聚己内酯 (PCL) 纳米颗粒可以开辟新的研究途径，有可能降低副作用并改善吉非替尼在 NSCLC 治疗中的效果。
For non-small cell lung cancer (NSCLC) treatment, a BCS class II drug, Gefitinib, was widely used. Due to poor bioavailability, uncontrollable drug release, Gefitinib witnessed side effects. To circumvent such associated problems, optimized Gefitinib encapsulated polycaprolactone (PCL) nanoparticles with three different molecular weights of PCL (average Mn similar to 10,000, Mn similar to 45,000 & Mn similar to 80,000) were developed using Box-Behnken design while understanding the influence of critical process parameters of the nanoparticles. For morphological characterizations, SEM, TEM, AFM were used. Hemocompatibility, platelet aggregation, and erythrocyte membrane integrity tests were used to test nanoparticles for biocompatibility; excellent biocompatibility was reported during these tests. The in-vitro drug release studies confirmed that Gefitinib-PCL(10,000)NPs, Gefitinib-PCL(45,000)NPs, and Gefitinib-PCL80,000 NPs, show significant initial burst effects, and later nanoparticles possessed zero-order kinetics. The genotoxicity of PCL nanoparticles was assessed by cytokinesis-block micronucleus (CBMN) assay, indicating DNA damage in NCI-H460 cell and micronuclei and nuclear buds' formation. Further, reactive oxygen species studies, MTT cytotoxicity assays at 24 & 48 h, stability, in-vitro cellular uptake of optimized fluorescent Gefitinib PCL(80,000)NPs, and apoptosis studies were also carried out. As a result, investigating stable Gefitinib-loaded poly-caprolactone (PCL) nanoparticles could open up new research avenues, potentially lowering side effects and improving Gefitinib's profile in the treatment of NSCLC.