Department of Biotechnology, Chemistry, and Pharmacy, University of Siena, Siena, Italy.
Institute of Clinical Physiology, Italian National Research Council (CNR), Pisa, Italy.
Drug Dev Res. 2024 Feb;85(1):e22158. doi: 10.1002/ddr.22158.
Glioblastoma multiforme (GBM) is one of the most aggressive malignancies with a high recurrence rate and poor prognosis. Theranostic, combining therapeutic and diagnostic approaches, arises as a successful strategy to improve patient outcomes through personalized medicine. Src is a non-receptor tyrosine kinase (nRTK) whose involvement in GBM has been extensively demonstrated. Our previous research highlighted the effectiveness of the pyrazolo[3,4-d]pyrimidine SI306 and its more soluble prodrug CMP1 as Src inhibitors both in in vitro and in vivo GBM models. In this scenario, we decided to develop a theranostic prodrug of SI306, ProSI-DOTA( Ga) 1, which was designed to target GBM cells after hydrolysis and follow-up on the disease's progression and improve the therapy's outcome. First, the corresponding nonradioactive prodrug 2 was tested to evaluate its ADME profile and biological activity. It showed good metabolic stability, no inhibition of CYP3A4, suboptimal aqueous solubility, and slight gastrointestinal and blood-brain barrier passive permeability. Compound 2 exhibited a drastic reduction of cell vitality after 72 h on two different GBM cell lines (GL261 and U87MG). Then, 2 was subjected to complexation with the radionuclide Gallium-68 to give ProSI-DOTA( Ga) 1. The cellular uptake of 1 was evaluated on GBM cells, highlighting a slight but significant time-dependent uptake. The data obtained from our preliminary studies reflect the physiochemical properties of 1. The use of an alternative route of administration, such as the intranasal route, could overcome the physiochemical limitations and enhance the pharmacokinetic properties of 1, paving the way for its future development.
多形性胶质母细胞瘤（GBM）是一种侵袭性很强的恶性肿瘤，具有高复发率和预后不良的特点。治疗诊断一体化（Theranostics）是一种将治疗和诊断方法相结合的策略，旨在通过个体化医疗改善患者的治疗效果。Src 是一种非受体酪氨酸激酶（nRTK），其在 GBM 中的作用已被广泛证实。我们之前的研究强调了吡唑并[3,4-d]嘧啶类 Src 抑制剂 SI306 及其更具水溶性的前药 CMP1 在体外和体内 GBM 模型中的有效性。在此背景下，我们决定开发 SI306 的治疗诊断一体化前药 ProSI-DOTA( Ga)1，旨在水解后靶向 GBM 细胞，并跟踪疾病的进展，改善治疗效果。首先，我们测试了相应的非放射性前药 2，以评估其 ADME 特征和生物学活性。结果表明，2 具有良好的代谢稳定性，不会抑制 CYP3A4，水溶解度稍差，胃肠道和血脑屏障的被动渗透性也稍差。在两种不同的 GBM 细胞系（GL261 和 U87MG）中，2 在 72 小时后可显著降低细胞活力。然后，我们将 2 与放射性核素镓-68 络合，得到 ProSI-DOTA( Ga)1。我们在 GBM 细胞上评估了 1 的细胞摄取情况，结果表明，1 的摄取具有轻微但显著的时间依赖性。我们的初步研究结果反映了 1 的物理化学性质。通过使用替代给药途径，如鼻腔途径，可以克服物理化学限制，增强 1 的药代动力学性质，为其未来的发展铺平道路。
