Sadat Sams M A, Wuest Melinda, Paiva Igor M, Munira Sirazum, Sarrami Nasim, Sanaee Forughalsadat, Yang Xiaoyan, Paladino Marco, Binkhathlan Ziyad, Karimi-Busheri Feridoun, Martin Gary R, Jirik Frank R, Murray David, Gamper Armin M, Hall Dennis G, Weinfeld Michael, Lavasanifar Afsaneh
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada.
Department of Oncology, Cross Cancer Institute, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.
Front Oncol. 2021 Dec 23;11:772920. doi: 10.3389/fonc.2021.772920. eCollection 2021.
Inhibition of the DNA repair enzyme polynucleotide kinase/phosphatase (PNKP) increases the sensitivity of cancer cells to DNA damage by ionizing radiation (IR). We have developed a novel inhibitor of PNKP, i.e., A83B4C63, as a potential radio-sensitizer for the treatment of solid tumors. Systemic delivery of A83B4C63, however, may sensitize both cancer and normal cells to DNA damaging therapeutics. Preferential delivery of A83B4C63 to solid tumors by nanoparticles (NP) was proposed to reduce potential side effects of this PNKP inhibitor to normal tissue, particularly when combined with DNA damaging therapies. Here, we investigated the radio-sensitizing activity of A83B4C63 encapsulated in NPs (NP/A83) based on methoxy poly(ethylene oxide)--poly(α-benzyl carboxylate-ε-caprolactone) (mPEO--PBCL) or solubilized with the aid of Cremophor EL: Ethanol (CE/A83) in human HCT116 colorectal cancer (CRC) models. Levels of γ-H2AX were measured and the biodistribution of CE/A83 and NP/A83 administered intravenously was determined in subcutaneous HCT116 CRC xenografts. The radio-sensitization effect of A83B4C63 was measured following fractionated tumor irradiation using an image-guided Small Animal Radiation Research Platform (SARRP), with 24 h pre-administration of CE/A83 and NP/A83 to Luc/HCT116 bearing mice. Therapeutic effects were analyzed by monitoring tumor growth and functional imaging using Positron Emission Tomography (PET) and [F]-fluoro-3-deoxy-3-L:-fluorothymidine ([F]FLT) as a radiotracer for cell proliferation. The results showed an increased persistence of DNA damage in cells treated with a combination of CE/A83 or NP/A83 and IR compared to those only exposed to IR. Significantly higher tumor growth delay in mice treated with a combination of IR and NP/A83 than those treated with IR plus CE/A83 was observed. [F]FLT PET displayed significant functional changes for tumor proliferation for the drug-loaded NP. This observation was attributed to the higher A83B4C63 levels in the tumors for NP/A83-treated mice compared to those treated with CE/A83. Overall, the results demonstrated a potential for A83B4C63-loaded NP as a novel radio-sensitizer for the treatment of CRC.
抑制DNA修复酶多核苷酸激酶/磷酸酶（PNKP）可提高癌细胞对电离辐射（IR）所致DNA损伤的敏感性。我们已开发出一种新型的PNKP抑制剂，即A83B4C63，作为一种潜在的放射增敏剂用于实体瘤治疗。然而，A83B4C63的全身给药可能会使癌细胞和正常细胞都对DNA损伤性治疗敏感。有人提出通过纳米颗粒（NP）将A83B4C63优先递送至实体瘤，以减少这种PNKP抑制剂对正常组织的潜在副作用，尤其是在与DNA损伤疗法联合使用时。在此，我们在人HCT116结直肠癌（CRC）模型中研究了基于甲氧基聚（环氧乙烷）-聚（α-苄基羧酸酯-ε-己内酯）（mPEO-PBCL）封装在NP中的A83B4C63（NP/A83）或借助聚氧乙烯蓖麻油：乙醇（CE/A83）溶解的A83B4C63的放射增敏活性。测量了γ-H2AX水平，并在皮下HCT116 CRC异种移植瘤中测定了静脉注射的CE/A83和NP/A83的生物分布。在使用图像引导的小动物辐射研究平台（SARRP）对肿瘤进行分次照射后，测量了A83B4C63的放射增敏效果，在给携带Luc/HCT116的小鼠预先给药CE/A83和NP/A83 24小时后进行照射。通过监测肿瘤生长并使用正电子发射断层扫描（PET）和[F] -氟-3-脱氧-3-L：-氟胸苷（[F]FLT）作为细胞增殖的放射性示踪剂进行功能成像来分析治疗效果。结果显示，与仅接受IR照射的细胞相比，用CE/A83或NP/A83与IR联合处理的细胞中DNA损伤的持续时间增加。观察到与用IR加CE/A83处理的小鼠相比，用IR和NP/A83联合处理的小鼠肿瘤生长延迟明显更高。[F]FLT PET显示载药NP对肿瘤增殖有显著的功能变化。这一观察结果归因于与用CE/A83处理的小鼠相比，NP/A83处理的小鼠肿瘤中A83B4C63水平更高。总体而言，结果表明负载A
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