Design of a novel nucleus-targeted NLS-KALA-SA nanocarrier to delivery poorly water-soluble anti-tumor drug for lung cancer treatment.
Design of a novel nucleus-targeted NLS-KALA-SA nanocarrier to delivery poorly water-soluble anti-tumor drug for lung cancer treatment.
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DOI：
10.1016/j.xphs.2020.12.034
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发表时间：
2021-01
影响因子：
3.8
通讯作者：
Chengyun Yan;Weiguo Shi;Jiwei Gu;Robert J. Lee;Y. Zhang
中科院分区：
文献类型：
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作者：
Chengyun Yan;Weiguo Shi;Jiwei Gu;Robert J. Lee;Y. Zhang
本研究采用Fmoc固相合成法，以Kala肽（Kala peptide，KALA）、核定位信号（Nuclear Localization Signal，NLS）和硬脂酸（Stearic Acid，SA）为原料，设计了一种新型核靶向纳米载体（NLS-KALA-SA，NKSN）。以姜黄素（CUR）、紫杉醇（PTX）、人参皂苷化合物K（CK）作为难溶性抗肿瘤药物模型，采用透析法制备载药纳米粒（CUR/NKSN、PTX/NKSN、CK/NKSN），测定其理化性质并评价其抗肿瘤活性。NLS-KALA-SA纳米颗粒呈球形，平均尺寸为76.4 ± 7.6 mm，zeta电位为43.7 ± 5.8 mV。载药纳米粒的包封率和载药量分别在86.1%和17.1%以上，并具有缓释作用。生物分布和细胞摄取研究表明，PTX/NKSN主要分布在荷瘤小鼠的肿瘤部位，而香豆素-6（C6）负载的NLS-KALA-SA纳米粒（C6/NKSN）主要聚集在A549细胞的细胞核中。Western blot结果显示，PTX/NKSN能显著抑制A549细胞Bcl-2的表达，增强Bcl-2和Caspase-3的表达。细胞凋亡和抗肿瘤活性研究表明，PXT/NKSN能更明显地诱导A549细胞凋亡，PTX/NKSN对A549荷瘤小鼠的治疗效果优于游离PTX，且毒性较轻。结果表明，NLS-KALA-SA纳米粒系统由于其长循环特性和肿瘤靶向性，可以增强药物的抗肿瘤作用，降低组织毒性，为肺癌的治疗提供了一种有希望的策略。
In this study, we designed a novel nucleus-targeted nanocarrier (NLS-KALA-SA, NKSN) consisting of Kala peptide (KALA), nuclear localization signal (NLS) and stearic acid (SA) using Fmoc solid phase synthesis method. We chose Curcumin (CUR), Paclitaxel (PTX), Ginsenoside compound K(CK) as models of poorly water-soluble antitumor drugs, The drugs loaded NLS-KALA-SA nanoparticles (CUR/NKSN, PTX/NKSN, CK/NKSN) were obained by the dialysis method, their physicochemical properties were determined and antitumor activity were evaluated. The NLS-KALA-SA nanoparticles were spherical shaped with an average size of 76.4 ± 7.6 mm and a zeta potential of 43.7 ± 5.8 mV. The drug-loaded NLS-KALA-SA nanoparticles were above 86.1% and 17.1% in entrapment efficiency and drug loading capacity, and had sustained drug release behavior. Biodistribution and cellular uptake study exhibited that PTX/NKSN mainly distributed in tumor site of A549-bearing mice, and coumarin-6(C6) loaded NLS-KALA-SA nanoparticle (C6/NKSN) was predominantly accumulated in the nucleus of A549 cells. Western blot analysis indicated that PTX/NKSN could more remarkably inhibitBcl-2expression and enhance the expression ofBaxandCaspase-3as compared to the controls in A549 cells. Cell apoptosis and antitumor activity study showed that PXT/NKSN could more obviously induce apoptosis of A549 cells compared with free PXT, the PTX/NKSN administration was more effective than free PTX for lung cancer treatment and displayed mild toxicity in A549-bearing mice. The results demonstrates that the NLS-KALA-SA nanoparticles system could enhance the antitumor effects of the encapsulated drug and reduce tissue toxicity due to its long circulating properties and tumor targeting, which might provide a promising strategy for lung cancer treatment.