Interdisciplinary Nanotechnology Centre, Aligarh Muslim University, Aligarh, UP, 202002, India.
Interdisciplinary Biotechnology Unit, Aligarh Muslim University, Aligarh, India.
Sci Rep. 2024 Nov 4;14(1):26610. doi: 10.1038/s41598-024-77868-8.
Immunotherapy is a promising treatment for cancer that aims to boost the immune system's response to cancer cells. This can be achieved by blocking Programmed cell death protein 1/Programmed death-ligand 1 (PD1/PDL1), which activates T cells. In this work, the aim was to find high-affinity drugs against PDL1 using computational tools and conjugate nanoparticles with them. The cytotoxic activity of the nanoparticle conjugated drugs was then tested. The screening of 100,000 drugs from the ZINC database and FDA-approved drugs was done computationally. The physicochemical properties and toxicity of the drugs were analyzed using SwissADME and ProTox-II, respectively. Silver nanoparticles (AgNPs) and gold nanoparticles (AuNPs) were synthesized using extracts of Catharanthus roseus flowers and Juglans regia shells, respectively. The characterization of AgNPs and AuNPs was performed using UV-Vis spectroscopy, X-ray diffraction (XRD), and Fourier transform infrared spectroscopy (FTIR). Their conjugation with the drugs Irinotecan, Imatinib, and Methotrexate was also confirmed using UV-Vis, FTIR, and Dynamic light scattering (DLS). The top screened drugs were ZINC1098661 and 3 FDA-approved drugs (Irinotecan, Imatinib, and Methotrexate). Docking studies revealed that Irinotecan had the highest binding affinity towards PDL1 when conjugated with silver nanoparticles (AgNPs) and gold nanoparticles (AuNPs). The Irinotecan-PDL1 complex was confirmed as the most stable through molecular dynamics simulations. The result of the methylthiazol tetrazolium (MTT) assay showed that conjugated AgNPs and AuNPs with Irinotecan had a higher toxic effect on the A549 cancer cell line than AgNPs and AuNPs conjugated with Imatinib. This study provides a promising avenue for further investigation and development of nanoparticle-drug conjugates as a potential cancer immunotherapy strategy.
免疫疗法是一种有前途的癌症治疗方法，旨在增强免疫系统对癌细胞的反应。这可以通过阻断程序性细胞死亡蛋白 1/程序性死亡配体 1（PD1/PDL1）来实现，PD1/PDL1 可以激活 T 细胞。在这项工作中，目的是使用计算工具找到针对 PDL1 的高亲和力药物，并将它们与共轭纳米颗粒结合。然后测试了纳米颗粒共轭药物的细胞毒性活性。通过计算从 ZINC 数据库和 FDA 批准的药物中筛选了 10 万个药物。使用 SwissADME 和 ProTox-II 分别分析了药物的物理化学性质和毒性。使用长春花和胡桃壳的提取物分别合成了银纳米颗粒（AgNPs）和金纳米颗粒（AuNPs）。通过紫外-可见光谱、X 射线衍射（XRD）和傅里叶变换红外光谱（FTIR）对 AgNPs 和 AuNPs 的特性进行了表征。还使用紫外-可见光谱、FTIR 和动态光散射（DLS）证实了它们与伊立替康、伊马替尼和甲氨蝶呤的结合。筛选出的前 10 名药物是 ZINC1098661 和 3 种 FDA 批准的药物（伊立替康、伊马替尼和甲氨蝶呤）。对接研究表明，当伊立替康与银纳米颗粒（AgNPs）和金纳米颗粒（AuNPs）结合时，具有最高的与 PDL1 的结合亲和力。通过分子动力学模拟证实伊立替康-PDL1 复合物是最稳定的。噻唑蓝（MTT）试验的结果表明，与伊立替康共轭的 AgNPs 和 AuNPs 对 A549 癌细胞系的毒性作用高于与伊马替尼共轭的 AgNPs 和 AuNPs。这项研究为进一步研究和开发作为潜在癌症免疫疗法策略的纳米药物缀合物提供了有前途的途径。
