尽管 MYCN 被认为是不可成药的靶点，但 MYCN 的改变会导致许多儿童和成人癌症的预后不良。新型 MYCN 特异性抑制剂 BGA002 是一种与核定位信号肽共价结合的反基因肽核酸寡核苷酸。在本研究中，我们使用新型特异性酶联免疫吸附测定对小鼠单次和重复给药后的 BGA002 药代动力学 (PK) 进行了表征。血浆中的 BGA002 浓度表现出线性 PK，在测试的剂量水平上剂量成比例增加，并且男性和女性之间以及静脉内和皮下给药途径之间的暴露相似。重复给药导致血浆中没有蓄积。 [14C]-放射性标记的 BGA002 单次皮下注射后 7 天的生物分布显示出广泛的组织和器官分布（表明具有到达原发肿瘤和多个身体部位转移的潜在能力），在肾、肝、脾、淋巴中浓度较高淋巴结、肾上腺和骨髓。值得注意的是，我们证明，在三种 MYCN 扩增小鼠模型（神经母细胞瘤、横纹肌肉瘤和小细胞肺癌）中重复全身给药后，BGA002 集中在肿瘤中，导致肿瘤重量显着减轻。考虑到 BGA002 的现有安全性，这些数据支持对 BGA002 在 MYCN 阳性肿瘤患者中的进一步评估。

Although MYCN has been considered an undruggable target, MYCN alterations confer poor prognosis in many pediatric and adult cancers. The novel MYCN-specific inhibitor BGA002 is an antigene peptide nucleic acid oligonucleotide covalently bound to a nuclear localization signal peptide. In the present study, we characterized the pharmacokinetics (PK) of BGA002 after single and repeated administration to mice using a novel specific enzyme-linked immunosorbent assay. BGA002 concentrations in plasma showed linear PK, with dose proportional increase across the tested dose levels and similar exposure between male and female and between intravenous and subcutaneous route of administration. Repeated dosing resulted in no accumulation in plasma. Biodistribution up to 7 days after single subcutaneous administration of [14C]-radiolabeled BGA002 showed broad tissues and organ distribution (suggesting a potential capability to reach primary tumor and metastasis in several body sites), with high concentrations in kidney, liver, spleen, lymph nodes, adrenals, and bone marrow. Remarkably, we demonstrated that BGA002 concentrates in tumors after repeated systemic administrations in three mouse models with MYCN amplification (neuroblastoma, rhabdomyosarcoma, and small-cell lung cancer), leading to a significant reduction in tumor weight. Taking into account the available safety profile of BGA002, these data support further evaluation of BGA002 in patients with MYCN-positive tumors.