Quaternized Chitosan–Ferulic Acid-Based Nanomicelles for Dimethoxycurcumin Delivery and Synergistic Colorectal Adenocarcinoma Therapy with 5-Fluorouracil

Quaternized chitosan derivatives conjugated with naturally occurring medicinal compounds have emerged as promising drug-delivery vehicles, exhibiting properties such as site-specificity, enhanced permeation into cancer cells, and reduced efflux of encapsulated drugs. In this study, ferulic acid (FA) was conjugated with quaternized chitosan (QCS) and used for the encapsulation of dimethoxycurcumin (DMC). The resulting nanomicelles were evaluated for activity against colorectal adenocarcinoma. The conjugates were obtained in 74% yield and structurally characterized by FTIR, proton NMR, DSC, and XRD. The DMC-loaded FA-QCS nanomicelles exhibited a spherical morphology under transmission electron microscopy, an average size of approximately 224.63 ± 2.49 nm to 270.6 ± 8.45 nm with a positive surface charge around +30 mV and an entrapment efficiency of 65.57%. The nanomicelles exhibited pH-responsive drug release, with maximum release at pH 5.5, which mimics the tumor microenvironment. In anticolorectal adenocarcinoma evaluations, the DMC-loaded micelles showed selective cytotoxicity and enhanced internalization in the colorectal adenocarcinoma cell lines (HT-29), with a significantly lower IC₅₀ value (0.99 ± 0.16 μg/mL) than that of free DMC (5.43 ± 0.86 μg/mL), inducing cell cycle arrest at the G2/M phase and promoting apoptosis. Notably, the DMC-loaded nanomicelles exhibited reduced toxicity toward the normal fibroblast cell line (L929) compared to pure DMC. Furthermore, cotreatment of DMC-loaded nanomicelles and 5-fluorouracil (5-FU) significantly enhanced anticancer efficacy through synergism (combination index < 1). Overall, this study supports quaternized chitosan and ferulic acid conjugates as potential drug-delivery vehicles that can encapsulate anticancer drug candidates and facilitate combination treatment strategies with chemotherapeutic agents such as 5-FU. However, further mechanistic anticancer and cytotoxic studies are warranted using tumor-bearing animal models and chemotherapy-resistant cell lines.