Co-encapsulated nanoparticles of Erlotinib and Quercetin for targeting lung cancer through nuclear EGFR and PI3K/AKT inhibition
Co-encapsulated nanoparticles of Erlotinib and Quercetin for targeting lung cancer through nuclear EGFR and PI3K/AKT inhibition
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DOI：
10.1016/j.colsurfb.2021.112305
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发表时间：
2022-01-05
影响因子：
5.8
通讯作者：
Sistla, Ramakrishna
中科院分区：
文献类型：
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作者：
Ganthala, Parimala Devi;Alavala, Sateesh;Sistla, Ramakrishna
基于厄洛替尼的EGFR靶向治疗已被证明对非小细胞肺癌（NSCLC）有显著的临床改善。然而，厄洛替尼（Ertb）的抗癌活性受到Ertb耐药性发展的限制，并对临床医生和患者提出了挑战。为了探索更好的治疗策略，我们评估了Ertb与不同天然产物的组合。我们确定，与Ertb与非瑟酮/鼠尾草酸/木犀草素相比，Ertb和槲皮素（Quer）组合对A549和NCI H460细胞更具协同作用。为了进一步提高疗效，克服游离药物的局限性，以壳聚糖-MA-TPGS聚合物为载体，采用热均质法制备Ertb和Quer固体脂质纳米粒。载药纳米颗粒（NP）显示出高包封率（77% Ertb和71.4% Quer）以及87.3 +/- 0.78 nm的小粒径和正zeta电位+13.4 +/- 1.12 mV。在pH 5.5时，Ertb和Quer以最高水平释放。我们发现，EQNPs可降低P-gp和nEGFR的表达。EQNPs增加Ertb和Quer的摄取，并诱导Ertb耐药的A549/ER细胞凋亡。此外，体内EQNP制剂显示肺组织中纳米颗粒的摄取增加，并显著降低nEGFR的表达。因此，EQNP可能被开发为具有最小副作用的NSCLC治疗靶向药物，以改善NSCLC患者的生活质量和生存期。
Erlotinib-based EGFR targeted therapy has proven significant clinical improvement against non-small cell lung cancer (NSCLC). However, the anticancer activity of Erlotinib (Ertb) is limited by the development of Ertb resistance and possess a challenge to clinicians and patients. To explore a better therapeutic strategy, we evaluated Ertb in combinations with different natural products. We identified that Ertb and Quercetin (Quer) combination is more synergistic against A549 and NCI H460 cells compared to Ertb with Fisetin/Carnosic acid/ Luteolin. To further improve the efficacy and overcome the limitation of free therapeutics, Ertb and Quer loaded solid lipid nanoparticles (EQNPs) were prepared using Chitosan-MA-TPGS polymer by hot homogenization method. The drug-loaded nanoparticles (NPs) have shown high encapsulation efficiency (77% Ertb and 71.4% Quer) as well as small particle size of 87.3 +/- 0.78 nm and positive zeta potential + 13.4 +/- 1.12 mV. At pH 5.5, Ertb and Quer were released at their highest levels. We found that, EQNPs decreased the expression of Pglycoprotein (P-gp) and nuclear epidermal growth factor receptor (nEGFR). EQNPs increased the uptake of Ertb and Quer, and apoptosis induction in Ertb resistant A549/ER cells. Further, in vivo EQNPs formulation have shown increased uptake of nanoparticles in the lung tissue and significantly reduced the expression of nEGFR. Thus, EQNPs may be developed as a targeted medicine with minimum side effects for treatment of NSCLC to improve the quality of life and survival of NSCLC patients.