Stimuli-Responsive Multifunctional Nanomedicine for Enhanced Glioblastoma Chemotherapy Augments Multistage Blood-to-Brain Trafficking and Tumor Targeting

Martins, Cláudia; Araújo, Marco; Malfanti, Alessio; Pacheco, Catarina; Smith, Stuart J.; Ucakar, Bernard; Rahman, Ruman; Aylott, Jonathan W.; Préat, Véronique; Sarmento, Bruno

Abstract

Minimal therapeutic advances have been achieved over the past two decades for glioblastoma (GBM), which remains an unmet clinical need. Here, hypothesis-driven stimuli-responsive nanoparticles (NPs) for docetaxel (DTX) delivery to GBM are reported, with multifunctional features that circumvent insufficient blood-brain barrier (BBB) trafficking and lack of GBM targeting—two major hurdles for anti-GBM therapies. NPs are dual-surface tailored with a i) brain-targeted acid-responsive Angiopep-2 moiety that triggers NP structural rearrangement within BBB endosomal vesicles, and ii) L-Histidine moiety that provides NP preferential accumulation into GBM cells post-BBB crossing. In tumor invasive margin patient cells, the stimuli-responsive multifunctional NPs target GBM cells, enhance cell uptake by 12-fold, and induce three times higher cytotoxicity in 2D and 3D cell models. Moreover, the in vitro BBB permeability is increased by threefold. A biodistribution in vivo trial confirms a threefold enhancement of NP accumulation into the brain. Last, the in vivo antitumor efficacy is validated in GBM orthotopic models following intratumoral and intravenous administration. Median survival and number of long-term survivors are increased by 50%. Altogether, a preclinical proof of concept supports these stimuli-responsive multifunctional NPs as an effective anti-GBM multistage chemotherapeutic strategy, with ability to respond to multiple fronts of the GBM microenvironment.

Citation

Martins, C., Araújo, M., Malfanti, A., Pacheco, C., Smith, S. J., Ucakar, B., …Sarmento, B. (in press). Stimuli-Responsive Multifunctional Nanomedicine for Enhanced Glioblastoma Chemotherapy Augments Multistage Blood-to-Brain Trafficking and Tumor Targeting. Small, Article 2300029. https://doi.org/10.1002/smll.202300029

• Journal Article Type: Article
• Acceptance Date: Feb 7, 2023
• Online Publication Date: Feb 28, 2023
• Deposit Date: Mar 14, 2023
• Publicly Available Date: Mar 16, 2023
• Journal: Small
• Print ISSN: 1613-6810
• Electronic ISSN: 1613-6829
• Publisher: Wiley
• Peer Reviewed: Peer Reviewed
• Article Number: 2300029
• DOI: https://doi.org/10.1002/smll.202300029
• Keywords: Blood‐brain barrier, drug delivery, dual‐ligand functionalization, glioblastoma, nanomedicine, stimuli‐responsiveness, targeting
• Public URL: https://nottingham-repository.worktribe.com/output/18222898
• Additional Information: Received: 2023-01-02; Published: 2023-02-28