Albumin/Hyaluronic Acid Gel Nanoparticles Loaded with a Pyrimidine-Based Drug for Potent Anticancer Activity

A pyrimidine-based compound (<b>PP</b>) was recently found to be a promising anticancer agent for colorectal and breast cancers. However, this compound exhibited low selectivity and poor water solubility. To address these challenges, albumin gel nanoparticles were used, where the gel matrix is formed by cross-linking of BSA molecules, allowing for a high concentration of this hydrophobic drug to be carried with no cytotoxicity to non-tumor cells. Functionalization with hyaluronic acid (HA) was employed to target CD44-overexpressing cancer cells, specifically triple-negative breast cancer (MDA-MB-231) and colorectal cancer cell lines (HCT 116). The gel nanoparticles present mean sizes below 250 nm, very low polydispersity, small aggregation tendency, and excellent colloidal stability in PBS buffer for a storage period of 30 days. Moreover, the drug-loaded particles showed high encapsulation efficiencies (above 85%) and sustained release profiles. Drug-loaded BSA/HA particles (<b>PP-HA-BSA-NPs</b>) revealed advantageous activity, presenting around 55% and 23% cell viability at a IC₅₀ drug concentration for triple-negative breast cancer (the most aggressive breast cancer subtype) and colorectal cancer (second leading cause of cancer-related deaths), respectively. In conclusion, these nanoparticles outperform the ones without HA, demonstrating target capabilities, while retaining the drug's anticancer activity and reducing the drug's toxicity. These results are promising for future in vivo assays and clinical translational applications.