Department of Pharmaceutics, Faculty of Pharmacy and Novel Drug Delivery Systems Research Centre, Isfahan University of Medical Sciences, Isfahan, Iran.
Department of Pharmaceutics, Faculty of Pharmacy and Novel Drug Delivery Systems Research Centre, Isfahan University of Medical Sciences, Isfahan, Iran.
Biomater Adv. 2023 Nov;154:213591. doi: 10.1016/j.bioadv.2023.213591. Epub 2023 Aug 15.
In the present study, gold nanoparticles functionalized with anti HER-2 aptamer were designed for effective targeted delivery of dasatinib (DSB) to breast cancer cells. Anti HER-2 aptamer attached to porous or plain gold nanoparticles were compared for dasatinib delivery. Activated drug with succinic anhydride and L-cysteine linker was used for conjugation of DSB to gold nanoparticles. The loading efficiency of the activated drug on plain and porous gold nanoparticles was 52 and 68 %, respectively, which was significantly more than the loading of free DSB in gold nanoparticles (1-2.5 %). The anti HER-2 aptamer was conjugated to porous gold nanoparticles loaded with the activated drug. Various characterization techniques such as FESEM, TEM, AFM, zeta potential and ICP-MS were used to confirm the binding of the drug to gold nanoparticles. HNMR and FTIR spectroscopic analyses were employed to examine the structural characteristics of the conjugated drug. These analytical techniques confirmed the successful incorporation of succinyl and thiol groups onto the drug molecule. The amount of aptamer binding to different types of gold nanoparticles was obtained from the intensity of the light emitted from the bands observed in electrophoresis gel and due to the presence of porosity in porous gold nanoparticles, the amount of aptamer conjugation on porous gold nanoparticles increased compared to plain ones. Cell cytotoxicity and cellular uptake were evaluated by MTT assay and TEM in BT-474 and MCF-7 cells. Aptamer-functionalized porous gold nanoparticles containing activated dasatinib showed higher cytotoxicity and cellular uptake than modified DSB-loaded nanoparticles and un-activated DSB. The combination of radiation therapy with the modified dasatinib attached to porous gold nanoparticles and aptamer demonstrated a notable reduction in the IC values for both the BT-474 and MCF-7 cell lines. Specifically, the IC value for the BT-474 cells decreased from 6.95 μM (for unmodified dasatinib) to 2.57 μM, while for the MCF-7 cells, it decreased from 13.97 μM to 8.57 μM. These findings indicate a significant improvement in the efficacy of the modified dasatinib compared to its unmodified counterpart when used in conjunction with radiation therapy.
在本研究中，设计了一种靶向递送达沙替尼（DSB）的载金纳米粒子，该载金纳米粒子表面修饰了抗 HER-2 适体。将与多孔或光滑金纳米粒子偶联的抗 HER-2 适体用于 DSB 的递送进行比较。用琥珀酸酐和 L-半胱氨酸连接子将活化药物与 DSB 连接，以提高药物在金纳米粒子上的载药量。与游离 DSB 在金纳米粒子上的载药量（1-2.5%）相比，载药的多孔金纳米粒子和光滑金纳米粒子的载药量分别为 52%和 68%。将抗 HER-2 适体与载有活化药物的多孔金纳米粒子偶联。利用 FESEM、TEM、AFM、Zeta 电位和 ICP-MS 等各种表征技术来证实药物与金纳米粒子的结合。利用 HNMR 和 FTIR 光谱分析来检测偶联药物的结构特征。这些分析技术证实了琥珀酰基和巯基成功地结合到药物分子上。从琼脂糖凝胶电泳中观察到的条带的光强度来获得不同类型金纳米粒子上的适体结合量，由于多孔金纳米粒子具有多孔性，因此多孔金纳米粒子上的适体偶联量比光滑金纳米粒子上的偶联量增加。通过 MTT 分析和 BT-474 和 MCF-7 细胞中的 TEM 评估细胞毒性和细胞摄取。载有活化的达沙替尼的适体功能化多孔金纳米粒子显示出比修饰的载有 DSB 的纳米粒子和未活化的 DSB 更高的细胞毒性和细胞摄取。与多孔金纳米粒子偶联的修饰的达沙替尼与放射治疗相结合，对 BT-474 和 MCF-7 细胞系的 IC 值有明显的降低。具体而言，BT-474 细胞的 IC 值从 6.95 μM（未修饰的达沙替尼）降低到 2.57 μM，而 MCF-7 细胞的 IC 值从 13.97 μM 降低到 8.57 μM。这些发现表明，与未修饰的达沙替尼相比，当与放射治疗联合使用时，修饰的达沙替尼的疗效有显著提高。
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