Formulation and evaluation of etoposide-loaded dextran polymeric nanoparticles fabricated with hyaluronic acid for the treatment of colorectal cancer using network pharmacology, in-silico, in-vitro, and in-vivo approaches.

Etoposide (ETP), a Biopharmaceutics Classification System class IV drug with poor aqueous solubility, demonstrates limited therapeutic efficacy against colorectal cancer (CRC) because of inferior absorption and off-target effects. To deliver drugs specifically to cancer cells that overexpress CD44, this study developed hyaluronic acid (HA)-functionalized dextran (DEX) polymeric nanoparticles (ETP-DEX-HA-NPs). Optimised nanoparticles (174.7 ± 3.2 nm, -12.83 ± 1.1 mV) demonstrated significant entrapment efficiency (62.75 ± 2.32%) and drug loading (55.64 ± 3.86%), with partial amorphization validated by FTIR, XRD, Raman, NMR and DSC analyses. The formulation exhibited prolonged, pH-responsive release, markedly improved solubility (p < 0.05), and greater cytotoxicity in HCT-116 cells (IC₅₀: 6.83 ± 0.35 µg/mL compared to 41.89 ± 1.02 µg/mL for free ETP). It facilitated CD44-mediated uptake, enhanced apoptosis, induced G2/M arrest, elevated ROS production and inhibited migration while preserving biocompatibility. Network pharmacology and molecular docking identified key interactions with CRC-related targets (e.g. TOP2A, BCL2). ETP-DEX-HA-NPs offer a promising, targeted nanoplatform that addresses ETP's limitations, boosting therapeutic efficacy and safety for CRC treatment.