Department of Pharmaceutical Sciences, College of Pharmacy, University of Cincinnati, Cincinnati, OH 45267-0514, USA.
Department of Chemistry, University of Cincinnati, Cincinnati, OH 45267-0514, USA.
Int J Mol Sci. 2021 Feb 19;22(4):2088. doi: 10.3390/ijms22042088.
RIDR-PI-103 is a novel reactive oxygen species (ROS)-induced drug release prodrug with a self-cyclizing moiety linked to a pan-PI3K inhibitor (PI-103). Under high ROS, PI-103 is released in a controlled manner to inhibit PI3K. The efficacy and bioavailability of RIDR-PI-103 in breast cancer remains unexplored. Cell viability of RIDR-PI-103 was assessed on breast cancer cells (MDA-MB-231, MDA-MB-361 and MDA-MB-453), non-tumorigenic MCF10A and fibroblasts. Matrigel colony formation, cell proliferation and migration assays examined the migratory properties of breast cancers upon treatment with RIDR-PI-103 and doxorubicin. Western blots determined the effect of doxorubicin ± RIDR-PI-103 on AKT activation and DNA damage response. Pharmacokinetic (PK) studies using C57BL/6J mice determined systemic exposure (plasma concentrations and overall area under the curve) and T of RIDR-PI-103. MDA-MB-453, MDA-MB-231 and MDA-MB-361 cells were sensitive to RIDR-PI-103 vs. MCF10A and normal fibroblast. Combination of doxorubicin and RIDR-PI-103 suppressed cancer cell growth and proliferation. Doxorubicin with RIDR-PI-103 inhibited p-AktS473, upregulated p-CHK1/2 and p-P53. PK studies showed that ~200 ng/mL (0.43 µM) RIDR-PI-103 is achievable in mice plasma with an initial dose of 20 mg/kg and a 10 h T. (4) The prodrug RIDR-PI-103 could be a potential therapeutic for treatment of breast cancer patients.
RIDR-PI-103 是一种新型的活性氧（ROS）诱导的药物释放前药，具有与泛 PI3K 抑制剂（PI-103）相连的自环化部分。在高 ROS 下，PI-103 以受控方式释放以抑制 PI3K。RIDR-PI-103 在乳腺癌中的疗效和生物利用度仍未得到探索。RIDR-PI-103 的细胞活力在乳腺癌细胞（MDA-MB-231、MDA-MB-361 和 MDA-MB-453）、非致瘤 MCF10A 和成纤维细胞上进行了评估。在经过 RIDR-PI-103 和阿霉素处理后，基质胶集落形成、细胞增殖和迁移实验研究了乳腺癌的迁移特性。Western blot 测定了阿霉素±RIDR-PI-103 对 AKT 激活和 DNA 损伤反应的影响。使用 C57BL/6J 小鼠进行的药代动力学（PK）研究确定了 RIDR-PI-103 的全身暴露（血浆浓度和总曲线下面积）和 T。与 MCF10A 和正常成纤维细胞相比，MDA-MB-453、MDA-MB-231 和 MDA-MB-361 细胞对 RIDR-PI-103 敏感。阿霉素与 RIDR-PI-103 的联合抑制了癌细胞的生长和增殖。阿霉素与 RIDR-PI-103 抑制了 p-AktS473，上调了 p-CHK1/2 和 p-P53。PK 研究表明，在初始剂量为 20mg/kg 且 T 为 10h 的情况下，RIDR-PI-103 在小鼠血浆中可达到约 200ng/mL（0.43µM）。（4）前药 RIDR-PI-103 可能是治疗乳腺癌患者的潜在治疗方法。
