School of Pharmacy, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland.
School of Pharmacy, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland.
Eur J Pharm Sci. 2024 Jan 1;192:106637. doi: 10.1016/j.ejps.2023.106637. Epub 2023 Nov 13.
Palbociclib, a cyclin-dependent kinase (CDK) 4/6 inhibitor, is currently used clinically for treating hormone receptor-positive and human epidermal growth factor receptor 2 negative breast cancer. Additionally, it has the potential to be utilized in the treatment of various tumors, including malignant glioblastoma. Previous research has indicated that palbociclib is a substrate for two efflux transporters, P-glycoprotein (P-gp; MDR1) and breast cancer-resistant protein (BCRP), which restrict the brain exposure of palbociclib. In the present study, our objective was to alter the brain distribution pattern of palbociclib by creating and assessing two novel prodrugs through in vitro, in situ, and in vivo evaluations. To this end, we synthesized two prodrugs of palbociclib by attaching it to the tyrosine promoiety at the para- (PD1) and meta-(PD2) position via a carbamate bond. We hypothesized that the prodrugs could bypass efflux transporter-mediated drug resistance by leveraging the l-type amino acid transporter (LAT1) to facilitate their transport across the blood-brain barrier (BBB) and into cancer cells, such as glioma cells that express LAT1. The compounds PD1 and PD2 did not show selective binding and had limited inhibitory effects on LAT1 in three cell lines (MCF-7, U87-MG, HEK-hLAT1). However, PD1 and PD2 demonstrated the ability to evade efflux mechanisms, and their in vitro uptake profiles were comparable to that of palbociclib, indicating their potential for effective cellular transport. In in situ and in vivo studies, brain uptake was not significantly improved compared to palbociclib, but the pharmacokinetic profiles showed encouraging enhancements. PD1 exhibited a higher AUC ratio, suggesting safer dosing, while PD2 showed favorable long-acting pharmacokinetics. Although our prodrug design did not significantly improve palbociclib brain delivery due to the potential size limitation of the prodrugs, the study provides valuable insights for future prodrug development and drug delivery strategies targeting specific transporters.
帕博西尼是一种细胞周期蛋白依赖性激酶（CDK）4/6 抑制剂，目前临床上用于治疗激素受体阳性和人表皮生长因子受体 2 阴性乳腺癌。此外，它还有可能用于治疗各种肿瘤，包括恶性神经胶质瘤。先前的研究表明，帕博西尼是两种外排转运蛋白，即 P-糖蛋白（P-gp；MDR1）和乳腺癌耐药蛋白（BCRP）的底物，这两种蛋白限制了帕博西尼在大脑中的暴露。在本研究中，我们的目的是通过体外、原位和体内评估来创建和评估两种新的前药，从而改变帕博西尼在大脑中的分布模式。为此，我们通过将帕博西尼连接到对（PD1）和间（PD2）位的酪氨酸前体上，通过碳酸酯键合成了两种帕博西尼前药。我们假设前药可以通过利用 L 型氨基酸转运体（LAT1）来绕过外排转运蛋白介导的药物耐药性，从而促进它们穿过血脑屏障（BBB）并进入癌细胞，如表达 LAT1 的神经胶质瘤细胞。在三种细胞系（MCF-7、U87-MG、HEK-hLAT1）中，化合物 PD1 和 PD2 没有显示出选择性结合，对 LAT1 的抑制作用有限。然而，PD1 和 PD2 表现出逃避外排机制的能力，其体外摄取谱与帕博西尼相当，表明它们具有有效的细胞转运能力。在原位和体内研究中，与帕博西尼相比，脑摄取没有显著改善，但药代动力学谱显示出令人鼓舞的增强。PD1 表现出更高的 AUC 比值，提示更安全的给药剂量，而 PD2 表现出良好的长效药代动力学特性。尽管由于前药的潜在大小限制，我们的前药设计没有显著改善帕博西尼的脑递药，但该研究为针对特定转运体的前药开发和药物递送策略提供了有价值的见解。
