Sunoqrot Suhair, Abusulieh Samah, Sabbah Dima
Department of Pharmacy, Faculty of Pharmacy, Al-Zaytoonah University of Jordan, Amman 11733, Jordan.
Biomedicines. 2024 Nov 24;12(12):2676. doi: 10.3390/biomedicines12122676.
: Dysregulation in phosphoinositide-3-kinase alpha (PI3Kα) signaling is implicated in the development of various cancers, including triple-negative breast cancer (TNBC). We have previously synthesized a series of N-phenyl-6-chloro-4-hydroxy-2-quinolone-3-carboxamides as targeted inhibitors against PI3Kα. Herein, two drug candidates, R7 and R11, were selected to be further investigated as a nanoparticle (NP) formulation against TNBC. : R7 and R11 were entrapped in D-α-tocopheryl poly(ethylene glycol) 1000 succinate (TPGS) polymeric NPs by nanoprecipitation. Following their physicochemical characterization, the anticancer activity of the compounds and their NP formulations was evaluated in the TNBC cell line MDA-MB-231 by conducting viability, uptake, and apoptosis assays, as well as penetration assays in a multicellular tumor spheroid model. : The NPs exhibited a particle size of 100-200 nm, excellent drug loading efficiencies, and sustained release under physiologic conditions. Viability assays revealed superior potency for the NP formulations, with IC values of 20 µM and 30 µM for R7- and R11-loaded NPs, respectively, compared to the free compounds, which exhibited IC values of 280 µM and 290 µM for R7 and R11, respectively. These results were attributed to the inherent antiproliferative activity of TPGS, as evidenced by the cytotoxicity of the drug-free NPs, as well as the enhanced cellular uptake enabled by the NP vehicle, as demonstrated by fluorescence microscopy imaging and flow cytometry measurements. Further investigations showed that the NPs promoted apoptosis via a mitochondrial-dependent pathway that involved the activation of proapoptotic caspases. Moreover, the NP formulations enhanced the penetration ability of the free compounds in multicellular tumor spheroids, causing a time- and concentration-dependent disruption of the spheroids. Our findings highlight the important role nanotechnology can play in improving the biopharmaceutical properties of new drug candidates and facilitating their in vivo translation.
磷脂酰肌醇-3-激酶α（PI3Kα）信号失调与包括三阴性乳腺癌（TNBC）在内的多种癌症的发生发展有关。我们之前合成了一系列N-苯基-6-氯-4-羟基-2-喹诺酮-3-甲酰胺作为针对PI3Kα的靶向抑制剂。在此，选择了两种候选药物R7和R11作为纳米颗粒（NP）制剂进一步研究其对TNBC的作用。：通过纳米沉淀法将R7和R11包裹于聚乙二醇1000琥珀酸维生素E（TPGS）聚合物纳米颗粒中。在对其进行理化性质表征后，通过进行活力、摄取、凋亡测定以及在多细胞肿瘤球体模型中的渗透测定，评估了这些化合物及其NP制剂在TNBC细胞系MDA-MB-231中的抗癌活性。：这些纳米颗粒的粒径为100 - 200 nm，具有优异的载药效率，并在生理条件下实现缓释。活力测定显示NP制剂具有更高的效力，负载R7和R11的纳米颗粒的IC值分别为20 μM和30 μM，而游离化合物R7和R11的IC值分别为280 μM和290 μM。这些结果归因于TPGS固有的抗增殖活性，无药物纳米颗粒的细胞毒性证明了这一点，同时NP载体促进了细胞摄取，荧光显微镜成像和流式细胞术测量也证明了这一点。进一步研究表明，纳米颗粒通过涉及促凋亡半胱天冬酶激活的线粒体依赖性途径促进凋亡。此外，NP制剂增强了游离化合物在多细胞肿瘤球体中的渗透能力，导致球体出现时间和浓度依赖性的破坏。我们的研究结果突出了纳米技术在改善新候选药物的生物药剂学性质并促进其体内转化方面可以发挥的重要作用。
