Local delivery of ibrutinib by folate receptor-mediated targeting PLGA-PEG nanoparticles to glioblastoma multiform: in vitro and in vivo studies

Glioblastoma multiforme (GBM) is a widespread and life-threatening kind of brain cancer, which has a high mortality rate. Ibrutinib, a Bruton's tyrosine kinase (BTK) inhibitor, irreversibly adheres to a conserved cysteine residue of two enzymes BTK and BMX, inhibiting their kinase activities which leads to suppression of the growth of glioma cells. This study synthesized PLGA-PEG-folate (PPF) polymer and subsequently encapsulated ibrutinib within PPF nanoparticles (IBT-PPF-NPs). HNMR spectra confirmed the synthesis of PPF polymer. The efficiency of IBT-PPF-NPs was 97 ± 2.26% with 8.8 ± 0.2% drug loading. The particle size was 208 ± 4.8nm. The IC50 value of free ibrutinib, IB-PPF-NPs, and ibrutinib encapsulated in PLGA NPs (IB-P-NPs) was 10.2, 7.6, and 10.13 µM in C6 cell lines, whereas in U-87 MG cells was 24.4, 16, and 25.2 µM respectively. The cellular uptake of FITC-PPF-NPs increased from 47.6% to 90.3% in C6 cells and from 55% to 97.3% in U-87 MG cells compared to FITC-P-NPs. The in vivo results indicate a significant reduction in tumor size in treatment groups in comparison to control groups, while the group that received the intratumoral injection of IB-PPF-NPs exhibited a greater reduction. The folate-targeting agent enhances the nanoparticles' effectiveness by promoting their uptake through the endocytosis pathway.