OICC Press Journal of Nanostructure in Chemistry 2193-8865 15 4 2025 08 31 Development of a Biocompatible PLGA-Based Nanoplatform for Targeted Delivery of Empagliflozin and Enhanced Cytotoxicity against Gastric Carcinoma Cells 10.57647/jnsc.2025.1503.14 EN Shu-Bo Tian Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, Shandong Province, China Bin Huo Department of Gastrointestinal Surgery, The Fourth People's Hospital of Jinan, Shandong Province, China Hao Liu Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, Shandong Province, China Shuai Kong Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, Shandong Province, China Ke-Shu Shan Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, Shandong Province, China https://orcid.org/0000-0001-5907-2189 Journal Article 2025 08 31 Gastric carcinoma remains a formidable global health challenge with limited therapeutic options and poor prognosis, necessitating the development of innovative treatment strategies. This study reports the design, synthesis, and comprehensive characterization of a novel biocompatible nanoplatform for the targeted delivery of empagliflozin (EMPA), a repurposed antidiabetic drug, to gastric carcinoma cells. The nanoplatform consists of a poly(lactic-co-glycolic acid) (PLGA) core encapsulating EMPA, with a surface functionalized with folic acid (FA) via a polyethylene glycol (PEG) linker (FA-EMPA-PLGA-NP) to actively target the overexpressed folate receptor (FR) on gastric cancer cells. The synthesized nanoparticles exhibited a uniform spherical morphology with a mean hydrodynamic diameter of approximately 165 nm, a low polydispersity index, and high encapsulation efficiency (>85%). A comprehensive suite of characterization techniques, including FTIR, XRD, SEM, TEM, XPS, and BET, confirmed the successful synthesis, surface modification, and amorphous encapsulation of the drug. In vitro drug release studies demonstrated a sustained, biphasic release profile that was significantly accelerated under acidic conditions (pH 5.5) compared to physiological pH (7.4), indicating a pH-responsive behavior beneficial for the tumor microenvironment. Confocal microscopy and flow cytometry analyses revealed significantly enhanced cellular uptake of FA-conjugated nanoparticles in FR-positive AGS gastric carcinoma cells compared to non-targeted counterparts. Consequently, the FA-EMPA-PLGA-NPs exhibited markedly superior cytotoxicity, with a significantly lower half-maximal inhibitory concentration (IC50) than both free EMPA and non-targeted nanoparticles. These findings demonstrate that the FA-EMPA-PLGA-NP system is a highly promising platform for the targeted therapy of gastric carcinoma, warranting further investigation in preclinical models.