Nanotechnology-Enabled Combination Strategies to Enhance 5-Fluorouracil-Based Cancer Chemotherapy

Cancer still ranks among the top causes of morbidity and mortality across the globe. Among the existing treatment modalities, including surgery, radiation therapy, biological therapy, and chemotherapy, 5-fluorouracil (5-FU) is one of the most widely employed drugs for the treatment of different solid cancers, such as colorectal, breast, pancreatic, and head and neck cancers. Although the drug has proven its efficacy in clinical settings, the therapeutic potential of 5-FU is greatly hampered by its rapid systemic clearance, severe dose-toxicity, lack of selectivity, and development of drug resistance. Therefore, there is a need to develop innovative approaches to improve its therapeutic effectiveness. Recently, nanotechnology has been recognized as a promising tool to address these issues by enhancing the stability, bioavailability, targetability, and controlled release of drugs. Different nanocarriers, such as liposomes, niosomes, nanostructured lipid carriers, solid lipid nanoparticles, hydrogels, polymeric nanoparticles, microparticles, and metal-organic frameworks, have been vastly explored to improve the pharmacokinetic and pharmacodynamic properties of 5-FU. In addition to improving 5-FU delivery, these nanocarriers also offer opportunities for combination therapy and for overcoming drug resistance. This review offers a comprehensive, comparative analysis of nanocarrier-based approaches for 5-FU delivery, focusing on their mechanistic benefits, preclinical efficacy, and translational potential. Moreover, ongoing clinical trials and combination therapies are reviewed to provide a translational perspective on the use of nanotechnology-based 5-FU chemotherapy. Overall, nanocarrier-based delivery offers a promising approach to improve the therapeutic efficacy and safety of 5-FU in cancer treatment.