Tyrosine kinase inhibitor-loaded zein nanoparticles with enhanced drug delivery and anticancer efficacy.

Tyrosine kinase inhibitors (TKIs) including erlotinib (Er) and gefitinib (Gef) can restrict the uncontrolled proliferation of cancer cells by inhibiting tyrosine kinases. However, their clinical application is limited by poor solubility and bioavailability; necessitating high doses that cause toxicity. Herein, we report the preparation of gum arabic-stabilized zein nanoparticles (GA-ZNPs) for delivering Er and Gef. The formulations exhibited particle sizes of 136.34 nm for Er-GA-ZNPs and 163.65 nm for Gef-GA-ZNPs with 86.4 % and 82.9 % encapsulation efficiencies, respectively. The drug-loaded GA-ZNPs demonstrated sustained release, with cumulative drug release reaching 75.8 % for Er and 65.7 % for Gef over 72 h. Uptake studies revealed a 2.45-2.7-fold increase in intracellular drug accumulation for GA-ZNPs formulations compared to free drugs. GA-ZNPs formulations significantly enhanced the cytotoxicity of the drugs on cancer cells, reducing IC₅₀ of free drugs by 1.58-2.35-fold for Er and 1.8-1.9-fold for Gef. Also, Er-GA-ZNPs and Gef-GA-ZNPs induced 1.5-2.4-fold and 1.2-2.7-fold higher apoptosis than free drugs in tested cancer cells, respectively. Mechanistic studies revealed higher ROS generation and mitochondrial membrane depolarization in cells treated with GA-ZNPs formulations. These findings suggest that GA-ZNPs-based formulations significantly improve the anticancer efficacy of TKIs, offering a promising approach for targeted cancer therapy.