Nanoparticle-based dual-triggered colon-targeted 5-fluorouracil tablets: A quality-by-design approach for improved colorectal cancer therapy

Abstract

Colorectal cancer (CRC) ranks among the top three most commonly diagnosed cancers worldwide and remains a leading cause of cancer-related deaths, accounting for nearly 10% of global cancer incidence. Despite advances in treatment, chemotherapy with 5-fluorouracil (5-FU) continues to be a mainstay; however, its rapid systemic clearance, limited tumor selectivity, and gastrointestinal toxicity significantly compromise therapeutic efficacy. To address these limitations, this study aimed to design and optimize a pH- and microflora-activated colon-targeted tablet containing 5-FU-loaded, folic acid-conjugated chitosan (FA-CS) nanoparticles for site-specific CRC therapy. The nanoparticles were prepared using ionic gelation with sodium tripolyphosphate (STPP) as a cross-linking agent and optimized through a Box–Behnken design (BBD). The optimized batch containing 0.45 mg/mL folic acid-conjugated chitosan, 0.50 mg/mL STPP, and 10.0 mg 5-FU exhibited a particle size of 232.5 nm, a polydispersity index of 0.307, and an entrapment efficiency of 81.3%. The nanoparticles were compressed into core tablets and sequentially coated with Eudragit E100, hydroxypropyl methylcellulose K15M (HPMC K15M), and Eudragit S100 to achieve delayed colon-targeted release. In vitro studies showed minimal drug release in gastric and intestinal media, followed by nearly complete release (approximately 96%) under simulated colonic conditions. The formulation also remained stable under accelerated conditions, supporting its potential for CRC therapy.