Design of Experiment-based Optimizationof Dual Drug-loaded Liquid CrystallineNanoparticles Containing 5-Fluorouraciland Melatonin
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Abstract
Introduction: Combination chemotherapy offers improved therapeutic outcomes by targeting multiple oncogenic
pathways simultaneously; however, co-delivery of drugs with contrasting physicochemical properties remains
a major formulation challenge. Liquid crystalline nanoparticles (LCNs) possess a unique bicontinuous cubic
architecture capable of encapsulating both hydrophilic and lipophilic agents within a single nanostructure. The
present study aimed to develop and optimize dual drug-loaded LCNs for the co-delivery of 5-fluorouracil (5-FU) and
melatonin (MEL) using a design of experiments-based approach. Materials and Methods: LCNs were prepared
by a top-down homogenization method employing glyceryl monooleate (GMO) and Poloxamer 407. A three-
factor Box–Behnken design was applied to evaluate the influence of GMO concentration, stabilizer concentration,
and homogenization speed on particle size, zeta potential, and entrapment efficiency. Characterization of the
optimized formulation was characterized by dynamic light scattering, X-ray diffraction (XRD), Field emission
scanning electron microscopy (FESEM), and in vitro drug release studies. Results and Discussion: Particle size
ranged from 102nm to 384.7nm, and statistical modeling confirmed significant effects of lipid concentration and
homogenization speed. The optimized formulation exhibited a particle size of 187.8 nm, zeta potential of −35.9 mV,
and entrapment efficiencies of 82.62% for 5-FU and 86.52% for MEL. XRD analysis revealed amorphous drug
incorporation, while FESEM confirmed nanoscale morphology. In vitro release studies demonstrated rapid release
of pure drugs, whereas LCNs exhibited a biphasic sustained release pattern extending up to 8 h. Conclusion: The
optimized LCNs system successfully enabled stable co-encapsulation and sustained release of hydrophilic and
lipophilic drugs, indicating its potential as a promising platform for synergistic anticancer therapy.
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