iRGD-Modified Peptide–Drug Conjugate Improves Brain Delivery and Antitumor Efficacy in Glioblastoma

Glioblastoma (GBM) remains the most aggressive primary brain tumor, with poor prognosis largely due to limited drug delivery across the blood–brain barrier (BBB) and insufficient intratumoral penetration. To address these challenges, we developed a tumor-targeting peptide–drug conjugate (PDC), iRGD–DTX, by covalently linking docetaxel (DTX) to the tumor-penetrating peptide iRGD through a succinic acid linker. The resulting conjugate was successfully synthesized with high purity (98.72%) and exhibited favorable physicochemical and metabolic stability. The iRGD ligand enables a multistep transport process involving integrin binding, proteolytic activation, and subsequent interaction with neuropilin-1 (NRP-1), thereby facilitating BBB penetration and tumor infiltration. Compared with free DTX, iRGD–DTX showed a 2.04-fold increase in cellular uptake and a 5.25-fold enhancement in BBB transport across an in vitro BBB model. These improvements translated into enhanced antiproliferative activity against U251 glioma cells, reducing the IC₅₀ from 176.6 to 84.0 nM after 48 h treatment. In orthotopic glioma-bearing mice, iRGD–DTX significantly increased brain accumulation, achieving a 4.09-fold higher brain Cmax and a 5.08-fold higher drug-targeting index than free DTX. Enhanced brain delivery resulted in superior tumor growth inhibition while maintaining favorable tolerability. Notably, the maximum tolerated dose increased from 15 mg/kg for free DTX to 40 mg/kg for iRGD–DTX. Overall, this study demonstrates that iRGD-mediated peptide–drug conjugation effectively improves BBB penetration, brain targeting, and antitumor efficacy of DTX, highlighting a promising strategy for the development of targeted therapeutics against GBM.