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

in Journal of drug targeting by Bahar Morshedi, Mehdi Esfandyari-Manesh, Fatemeh Atyabi, Mohammad Hossein Ghahremani, Rassoul Dinarvand

TLDR

  • A novel ibrutinib-loaded poly(lactic-co-glycolic acid)-polyethylene glycol-folate nanoparticle (IBT-PPF-NP) demonstrates enhanced efficacy and targeting ability against glioblastoma multiforme cells, offering potential as a therapeutic agent for this aggressive brain cancer.

Abstract

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.

Overview

  • The study aimed to develop and evaluate the efficacy of ibrutinib-loaded poly(lactic-co-glycolic acid)-polyethylene glycol-folate (PLGA-PEG-folate) nanoparticles (IBT-PPF-NPs) against glioblastoma multiforme (GBM) cells.
  • The study synthesized PLGA-PEG-folate polymer and encapsulated ibrutinib within the nanoparticles, which were evaluated for their efficiency, particle size, and ability to target cancer cells.
  • The primary objective of the study was to investigate the therapeutic potential of IBT-PPF-NPs against GBM cells and to explore their efficacy in vivo.

Comparative Analysis & Findings

  • The study found that the IC50 value of free ibrutinib and IBT-PPF-NPs was significantly lower compared to ibrutinib encapsulated in PLGA nanoparticles, indicating the enhanced efficacy of IBT-PPF-NPs.
  • The cellular uptake of FITC-PPF-NPs increased significantly compared to FITC-P-NPs in both C6 and U-87 MG cells, suggesting the improved targeting ability of PPF NPs.
  • The in vivo results showed a significant reduction in tumor size in treatment groups, with the group receiving intratumoral injection of IB-PPF-NPs exhibiting the greatest reduction, indicating the potential of IBT-PPF-NPs as a therapeutic agent for GBM.

Implications and Future Directions

  • The study's findings suggest that IBT-PPF-NPs may be a promising therapeutic agent for the treatment of GBM, offering improved efficacy and targeting ability compared to existing treatments.
  • Future studies should investigate the long-term toxicity and efficacy of IBT-PPF-NPs in various preclinical models to determine their clinical potential.
  • Exploring novel formulations and surface modifications of PPF NPs could further enhance their targeting ability and improve their therapeutic index.
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