Synthesis of a Gemcitabine Prodrug and its Encapsulation into Polymeric Nanoparticles for Improved Therapeutic Efficacy

Gemcitabine (GEM), a chemotherapeutic agent, is widely utilized in treating various neoplasm conditions, such as pancreatic, lung, breast, and ovarian cancers. However, its therapeutic effectiveness is often hindered by its hydrophilic nature, short half‐life and susceptibility to enzymatic degradation. To address these limitations, in this research, five new prodrugs of GEM were synthesized by conjugating its N‐4 amino group with five different acids [4‐decenoic acid (4Dec), lipoic acid (Lipo), lauric acid (Laur), 5‐benzyl N‐(tert‐butoxycarbonyl)‐ L‐glutamate (Glu), and decanoic acid (Dec)]. The anticancer potential of these prodrugs was evaluated using CCK‐8, annexin‐V FITC/propidium iodide staining, ROS, and mitochondrial membrane potential loss assays. Among the conjugates, 4Dec‐GEM demonstrated comparable cytotoxic activity to native GEM. To further enhance its therapeutic efficacy, 4Dec‐GEM was encapsulated in poly(lactic‐co‐glycolic acid) (PLGA) nanoparticles using single‐emulsion and high‐pressure homogenization, capitalizing on the lipophilicity of the prodrug. The developed nanoparticles were characterized by various techniques and demonstrated successful entrapment of 4Dec‐GEM inside PLGA nanoparticles. Finally, the cytotoxicity of developed nanoparticles demonstrated improved therapeutic efficacy as compared to native GEM in A549, MIA‐PaCa‐2 and PANC‐1 cancerous cell lines. Our study demonstrated that the combination of prodrug and nanoparticle can be a promising approach to augment the therapeutic efficacy of GEM.