Repurposing gemcitabine for glioblastoma treatment: The role of drug-conjugates and nanoparticles as drug delivery systems

Gemcitabine (GEM) repurposing for glioblastoma (GBM) therapy has been investigated as a fast-track approach to circumvent the drug resistance mediated by the O6-alkylguanine DNA alkyltransferase protein. This enzyme is associated with the modest outcomes of the current treatments. However, the use of GEM for brain tumor treatment is limited due to its short half-life, high toxicity, and poor permeability across cell membranes. To overcome these drawbacks, drug delivery systems (DDS) have been envisaged for GEM delivery to the brain, aiming to achieve an enhanced therapeutic effect with reduced off-target toxicity. Drug carriers offer promising opportunities for cancer treatment owing to their distinct advantages, including biocompatibility, increased stability, and precise targeting ability. Additionally, DDS show improved permeability and retention effects by leveraging the unique attributes of tumors and their microenvironments, thus exhibiting remarkable specificity and efficacy in cancer therapy. This review focuses, in particular, on the advances of drug-conjugates and nanoparticles employed for the brain tumor delivery of GEM, as these are one of the most studied DDS strategies. The advantages of the different proposed systems are here discussed, as their limitations and new emerging strategies to address these. The preclinical and clinical evidence of GEM efficacy for GBM treatment and the constraints of its administration are also discussed in this review.