Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana 500037, India.
Department of Pharmacoinformatic, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana 500037, India.
Int J Pharm. 2024 Nov 15;665:124672. doi: 10.1016/j.ijpharm.2024.124672. Epub 2024 Sep 7.
Dasatinib (DAB) has been explored for repurposing in the treatment of breast cancer (BC) due to its known effectiveness in treating leukemia, in addition to its role as a tyrosine kinase inhibitor. Gallic acid (GA) was chosen as a co-former due to its anticancer potential in BC, as demonstrated in several previous studies. DAB is a low-solubility drug, which is a significant hurdle for its oral bioavailability. To address this limitation, a DAB and GA co-amorphous (DAB-GA-CA) system was developed using liquid-assisted grinding and ball mill technology to enhance solubility, bioavailability, and anti-tumor efficacy. Physical characterization investigation revealed that the emergence of the halo diffractogram in PXRD, single glass transition temperature (T) value at 111.7 °C in DSC thermogram, and irregularly shaped blocks with loose, porous surfaces in SEM analysis indicated the formation of the DAB-GA-CA system at 1:1 M ratio. Furthermore, FTIR, Raman spectroscopy, in-silico molecular docking, and molecular dynamic studies confirmed the intermolecular hydrogen connections between DAB and GA. Moreover, the outcomes of the ligands (DAB and GA) and receptors (BCL-2, mTOR, estrogen receptor, and HER-2) docking studies demonstrated that both DAB and GA could interact with those receptors, leading to preventive action on BC cells. Additionally, the solubility and dissolution rate significantly improved at pH 6.8, and the permeability study indicated that DAB-GA-CA showed 1.9 times higher apparent permeability compared to crystalline DAB. Furthermore, in vitro cytotoxicity assessments of the DAB-GA-CA system revealed 3.42 times lower IC than free DAB. The mitochondrial membrane depolarization, apoptotic index, and reactive oxygen species formation in MCF-7 cells were also notably higher in the DAB-GA-CA system than in free DAB. Hence, this research suggests that the DAB-GA-CA system could substantially enhance oral delivery, solubility, and therapeutic efficacy.
达沙替尼（DAB）因其在治疗白血病方面的有效性，以及作为一种酪氨酸激酶抑制剂的作用，已被探索用于乳腺癌（BC）的再利用治疗。由于其在 BC 中的抗癌潜力，已在几项先前的研究中得到证实，因此选择没食子酸（GA）作为共晶形成剂。DAB 是一种低溶解度的药物，这对其口服生物利用度是一个重大障碍。为了解决这一限制，使用液体辅助研磨和球磨技术开发了 DAB 和 GA 共无定形（DAB-GA-CA）系统，以提高溶解度、生物利用度和抗肿瘤功效。物理特性研究表明，在 PXRD 中出现晕衍射图、DSC 热图谱中单玻璃化转变温度（T）值为 111.7°C，以及在 SEM 分析中呈现不规则形状的块状物，具有疏松、多孔的表面，表明在 1:1 M 比例下形成了 DAB-GA-CA 系统。此外，傅里叶变换红外光谱（FTIR）、拉曼光谱、分子对接和分子动力学研究证实了 DAB 和 GA 之间的分子间氢键连接。此外，配体（DAB 和 GA）和受体（BCL-2、mTOR、雌激素受体和 HER-2）对接研究的结果表明，DAB 和 GA 都可以与这些受体相互作用，从而对 BC 细胞起到预防作用。此外，在 pH 6.8 时，溶解度和溶解速率显著提高，渗透性研究表明，DAB-GA-CA 的表观渗透性比结晶 DAB 高 1.9 倍。此外，DAB-GA-CA 系统的体外细胞毒性评估显示，其 IC 比游离 DAB 低 3.42 倍。在 MCF-7 细胞中，线粒体膜去极化、凋亡指数和活性氧形成也明显高于游离 DAB。因此，这项研究表明，DAB-GA-CA 系统可以显著提高口服递送、溶解度和治疗效果。
