Mehinrad Parnian, Abdelfattah Ahmed, Sadat Sams M A, Shafaati Tanin, Elmenoufy Ahmed H, Jay David, West Frederick, Weinfeld Michael, Lavasanifar Afsaneh
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, T6G 2E1, Canada.
Department of Industrial Pharmacy, Faculty of Pharmacy, Assiut University, Assiut, 71526, Egypt.
Drug Deliv Transl Res. 2025 Jan 29. doi: 10.1007/s13346-024-01782-9.
In this study, a novel inhibitor of ERCC1/XPF heterodimerization, A4, was used as an inhibitor of repair for DNA damage by platinum-based chemotherapeutics. Nano-formulations of A4 were developed, using self-assembly of the following block copolymers: methoxy-poly(ethylene oxide)-block-poly(α-benzyl carboxylate-ε-caprolactone) (PEO-b-PBCL), methoxy-poly(ethylene oxide)-block-poly(ε-caprolactone) (PEO-b-PCL), or methoxy-poly(ethylene oxide)-block-poly (D, L, lactide) (PEO-b-PDLA 50-50). The nano-formulations were characterized for their average diameter, polydispersity, morphology, A4 encapsulation and in vitro release. The activity of A4 and its nano-formulation on the inhibition of ERCC1/XPF dimerization was investigated. The cytotoxicity of carboplatin and oxaliplatin in colorectal cancer (CRC) cell lines, without or with pre-treatment with A4 or its nanoparticle formulation was assessed by conducting colony forming as well as 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assays. Among the three nano-formulations of A4 under study, optimum properties were achieved with PEO-b-PBCL nanocarriers, showing an encapsulation efficiency of 83.1 ± 5.83%, loading content of 11.5 ± 0.37 w/w %, < 50% drug release within 24 hs, and an average diameter of < 150 nm. The chemo sensitizing effect of A4 and its nano-encapsulated counterparts were more noticeable when A4 was combined with carboplatin versus oxaliplatin. The results of cytotoxicity studies in HCT116 XPF cells confirmed the specificity of A4 through an XPF-dependent mechanism in the sensitization of these cells to carboplatin at concentrations below 0.5 μM. The result of the study shows great potential for A4 and its PEO-b-PBCL nano-formulation in sensitization of CRC to platinum-based chemotherapeutics.
在本研究中，一种新型的ERCC1/XPF异二聚体抑制剂A4被用作铂类化疗药物所致DNA损伤修复的抑制剂。利用以下嵌段共聚物的自组装制备了A4的纳米制剂：甲氧基聚（环氧乙烷）-嵌段-聚（α-苄基羧酸酯-ε-己内酯）（PEO-b-PBCL）、甲氧基聚（环氧乙烷）-嵌段-聚（ε-己内酯）（PEO-b-PCL）或甲氧基聚（环氧乙烷）-嵌段-聚（D，L-丙交酯）（PEO-b-PDLA 50-50）。对纳米制剂的平均直径、多分散性、形态、A4包封率和体外释放进行了表征。研究了A4及其纳米制剂对ERCC1/XPF二聚体抑制的活性。通过集落形成以及3-（4,5-二甲基噻唑-2-基）-2,5-二苯基-2H-四唑溴盐（MTT）试验，评估了卡铂和奥沙利铂在结直肠癌（CRC）细胞系中，在有无A4或其纳米颗粒制剂预处理情况下的细胞毒性。在所研究的三种A4纳米制剂中，PEO-b-PBCL纳米载体具有最佳性能，其包封率为83.1±5.83%，载药量为11.5±0.37 w/w%，24小时内药物释放<50%，平均直径<150 nm。当A4与卡铂联合使用时，A4及其纳米包封物的化疗增敏作用比与奥沙利铂联合使用时更明显。在HCT116 XPF细胞中的细胞毒性研究结果证实了A4在浓度低于0.5 μM时通过XPF依赖性机制使这些细胞对卡铂敏感的特异性。研究结果表明，A4及其PEO-b-PBCL纳米制剂在使CRC对铂类化疗药物敏感方面具有巨大潜力。
