Hyaluronic acid-carrageenan nanoparticles for targeted docetaxel delivery in colorectal cancer-optimized design and network pharmacology analysis using HCT116 cells and DMH-induced Wistar rats

The objective of this research was to produce nanoparticles composed of hyaluronic acid (HA) and carrageenan (CGR) for the targeted delivery of docetaxel (DTX) in the treatment of colorectal cancer (CRC), thereby improving drug stability, bioavailability, and efficacy through the Design of Experiments (DoE) and network pharmacology. DTX-HA-CGR-DTX nanoparticles were optimized using Design of Experiments for particle size and Zeta potential. Characterization encompassed stability, pH-responsive drug release, and cytotoxicity in HCT116 cells. Network pharmacology revealed the targets and pathways for DTX-CRC. The effectiveness of in vivo antitumor activity was evaluated in rat models of CRC induced by DMH. Hemolysis, platelet aggregation, and HET-CAM assays were used to evaluate biocompatibility. Pharmacokinetics assessed AUC and half-life. Optimized nanoparticles exhibited a size of 193 ± 2.5 nm and a zeta potential of −19.26 ± 1.3 mV, confirming their stability. pH-sensitive release (96.12 ± 3.45% at pH 5.5 compared to 69.35 ± 3.06% for free DTX) and increased cytotoxicity (IC50: 3.029 µg/mL) through CD44-mediated uptake were reported. Network analysis identified 53 DTX-CRC targets, suggesting involvement of PI3K/Akt, MAPK, and apoptosis pathways. In vivo, tumors significantly decreased with enhanced histology and increased apoptosis. Pharmacokinetics revealed a 570-fold increase in AUC (574.01 µg·h/mL) and a longer half-life (9.69 hours) compared to free DTX, and biocompatibility was verified (hemolysis <1%, no platelet aggregation). These results demonstrate that DTX-HA-CGR-DTX are a safe, targeted, and stable platform with improved therapeutic efficacy for colorectal cancer.