Design and characterization of beta-cyclodextrin/chitosan-coated zeolitic imidazolate framework-8 to enhance luteolin solubility and anticancer efficacy: bioinformatic and biologic assessment

Colorectal cancer remains a cause of cancer-related mortality, while luteolin, a flavonoid, is limited by poor aqueous solubility, rapid metabolism, and low bioavailability. This study developed a luteolin-loaded β-cyclodextrin/chitosan-coated zeolitic imidazolate framework-8 (Lut@β-CD/CS/ZIF-8) nanocarrier intended to improve drug retention, pH-responsive release, and anticancer activity against colorectal cancer cells. ZIF-8 nanoparticles were synthesized by room-temperature precipitation, coated sequentially with β-cyclodextrin and chitosan, crosslinked using sodium tripolyphosphate, and loaded with luteolin by post-synthetic incubation. Molecular docking using MOE 2024 investigated luteolin interactions with KRAS (PDB 6MBU), chitosan-binding protein (4ZXE), and VEGF (2VPF), with 5-fluorouracil as a computational comparator. FTIR, dynamic light scattering, zeta-potential analysis, pH-dependent surface-charge measurements, and FESEM characterized the formulation. Encapsulation efficiency and loading capacity were quantified spectrophotometrically; release was assessed by dialysis at pH 7.4, 6.5, and 5.5. HCT116 colorectal carcinoma and normal human dermal fibroblasts underwent MTT testing. Annexin V/PI flow cytometry, AO/EB microscopy, SOD activity, FRAP, and qRT-PCR for CASP3, SOD1, and IL6 evaluated cell-death and stress responses. The particles showed a hydrodynamic diameter of 228.95 ± 2.7 nm, a PDI of 0.139 ± 0.04, and a zeta potential of − 27.24 ± 0.32 mV, indicating a uniform nanoscale dispersion. Synthesis yield was 78.5 ± 3.2%. Measured luteolin retention increased with feed concentration, reaching 83.5 ± 1.44% encapsulation efficiency and 16.1 ± 1.53% loading capacity. Release was slower under physiological conditions and accelerated in acidic media, supporting pH-responsive behavior; model fitting was descriptive, with Higuchi favored at pH 7.4, Korsmeyer–Peppas at pH 6.5, and the lowest AIC assigned to Korsmeyer–Peppas at pH 5.5. In HCT116, free luteolin produced an IC 50 of 166.5 ± 12.3 µg/mL, whereas Lut@β-CD/CS/ZIF-8 reduced the IC 50 to 45.96 ± 2.3 µg/mL (approximately 3.6-fold greater potency; p < 0.001). The formulation IC 50 in HDF cells was 128.7 ± 8.4 µg/mL, yielding an HCT116/HDF selectivity index of 2.8. At 66 µg/mL, total apoptosis reached 48.9 ± 2.9%, compared with 1.3 ± 0.3% in controls. FRAP antioxidant capacity decreased to 0.578 ± 0.015 versus 0.801 ± 0.022 in controls. CASP3 and SOD1 transcripts increased 4.98-fold and 4.10-fold, respectively, while IL6 peaked at 10.92-fold at the intermediate dose. The dual-coated nanocarrier enhanced luteolin potency and apoptosis-associated responses in HCT116, with selectivity relative to HDF cells. Docking and characterization findings are supportive, not proof of KRAS inhibition, tumor targeting, or in vivo efficacy; validation remains necessary.