College of Pharmacy, Ajou University, Suwon 16499, Republic of Korea; Advanced Micro-Mechatronics Lab, Mechatronics Engineering, Jeju National University, Jeju City 63243, Republic of Korea.
Women's Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
Mater Sci Eng C Mater Biol Appl. 2020 Jun;111:110760. doi: 10.1016/j.msec.2020.110760. Epub 2020 Feb 19.
Nanoparticle-protein interactions under conditions mimicking physiology determine how nanoparticles (NPs) will behave inside blood vessels and, therefore, the overall outcome of the drug-delivery system. Here, for the first time, we explore the effects of bio-mimicking shear stress and protein corona conditions on novel active targeting of clickable fattigation nanoparticles (NPs) for cancer therapy. Active targeting dibenzocyclooctyne-functionalized biocompatible gelatin-oleic NPs (GON-DBCOs) via a bioorthogonal click reaction were prepared by the desolvation method for delivery of docetaxel (DTX) to lung and breast cancer models. The effect of shear stress (5 dyne/cm) and human serum albumin (HSA) protein corona on the cellular behavior of NPs was explored under a dynamic microfluidic system in lung (A549) and breast (MCF-7) cancer cell lines. The developed drug-loaded NPs had a particle size of 300 nm, a narrow size distribution, positive zeta potential, high encapsulation efficacy (72.4%), and spherical morphology. The particle size of the protein corona-coated NPs increased to 341 nm with a negative zeta potential. The inhibitory dose (IC) increased approximately 3- and 42-fold in A549 and MCF-7 cells, respectively, under dynamic microfluidic conditions compared to static conditions. Cellular uptake was significantly decreased in the presence of shear stress and a protein corona, compared with static conditions, in both lung (A549, **p < 0.01) and breast (MCF-7, *p < 0.05) cancer cell lines. Clathrin-and energy-dependent pathways were found to be involved in the cellular uptake of NPs. This study could serve as a vital tool for the evaluation of NPs under aggressive bio-mimicking conditions comprising shear stress and a protein corona to predict the in vivo performance of NPs and support the preclinical and clinical translation of NP drug delivery systems.
在模拟生理条件下的纳米颗粒-蛋白质相互作用决定了纳米颗粒（NPs）在血管内的行为方式，因此也决定了药物输送系统的整体效果。在这里，我们首次探索了生物模拟切变应力和蛋白质冠条件对新型点击化学修饰的脂肪化纳米颗粒（NPs）用于癌症治疗的主动靶向的影响。通过去溶剂法制备了主动靶向二苯并环辛炔功能化生物相容性明胶-油酸 NPs（GON-DBCOs），用于递送达托昔康（DTX）到肺癌和乳腺癌模型。在肺（A549）和乳腺癌（MCF-7）癌细胞系中的动态微流控系统中，研究了切变应力（5 达因/厘米）和人血清白蛋白（HSA）蛋白冠对 NPs 细胞行为的影响。所开发的载药 NPs 的粒径为 300nm，粒径分布较窄，具有正 zeta 电位，高包封效率（72.4%）和球形形态。带有蛋白质冠的 NPs 的粒径增加到 341nm，zeta 电位为负。与静态条件相比，在动态微流控条件下，A549 和 MCF-7 细胞中的抑制剂量（IC）分别增加了约 3 倍和 42 倍。与静态条件相比，在存在切变应力和蛋白质冠的情况下，A549（**p<0.01）和 MCF-7（*p<0.05）癌细胞系中细胞摄取显著减少。在细胞内摄取中发现网格蛋白和能量依赖性途径参与 NPs。这项研究可以作为在包括切变应力和蛋白质冠的侵袭性生物模拟条件下评估 NPs 的重要工具，以预测 NPs 的体内性能，并支持 NP 药物输送系统的临床前和临床转化。
