Abstract

Retinoid treatment is employed during residual disease treatment in neuroblastoma, where the aim is to induce neural differentiation or death in tumour cells. However, although therapeutically effective, retinoids have only modest benefits and suffer from poor pharmacokinetic properties. In vivo, retinoids induce CYP26 enzyme production in the liver, enhancing their own rapid metabolic clearance, while retinoid resistance in tumour cells themselves is considered to be due in part to increased CYP26 production. Retinoic acid metabolism blocking agents (RAMBAs), which inhibit CYP26 enzymes, can improve retinoic acid (RA) pharmacokinetics in pre-clinical neuroblastoma models. Here, we demonstrate that in cultured neuroblastoma tumour cells, RAMBAs enhance RA action as seen by morphological differentiation, AKT signalling and suppression of MYCN protein. Although active as retinoid enhancers, these RAMBAs are highly hydrophobic and their effective delivery in humans will be very challenging. Here, we demonstrate that such RAMBAs can be loaded efficiently into cationic liposomal particles, where the RAMBAs achieve good bioavailability and activity in cultured tumour cells. This demonstrates the efficacy of RAMBAs in enhancing retinoid signalling in neuroblastoma cells and shows for the first time that liposomal delivery of hydrophobic RAMBAs is a viable approach, providing novel opportunities for their delivery and application in humans.

摘要

在神经母细胞瘤的残留疾病治疗期间采用类视色素治疗，其目的是诱导肿瘤细胞的神经分化或死亡。然而，尽管在治疗上有效，类视色素仅具有适度的益处并且具有较差的药代动力学特性。体内，类维生素 A 诱导肝脏中 CYP26 酶的产生，增强其自身的快速代谢清除，而肿瘤细胞本身的类维生素 A 抗性被认为部分是由于 CYP26 产生增加。抑制 CYP26 酶的视黄酸代谢阻断剂 (RAMBA) 可以改善临床前神经母细胞瘤模型中的视黄酸 (RA) 药代动力学。在这里，我们证明了在培养的神经母细胞瘤肿瘤细胞中，RAMBA 增强了 RA 作用，如形态分化、AKT 信号传导和 MYCN 蛋白的抑制所见。尽管作为类视黄醇增强剂具有活性，但这些 RAMBA 具有高度疏水性，它们在人体中的有效递送将非常具有挑战性。在这里，我们证明了这种 RAMBA 可以有效地加载到阳离子脂质体颗粒中，其中 RAMBA 在培养的肿瘤细胞中具有良好的生物利用度和活性。这证明了 RAMBAs 在增强神经母细胞瘤细胞中类视黄醇信号传导方面的功效，并首次表明疏水性 RAMBAs 的脂质体递送是一种可行的方法，为其递送和在人类中的应用提供了新的机会。