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 AUCbrain/plasma 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.