MIL-100(Fe)-Magnetite-Chitosan nanocomposite for targeted EPR delivery: synthesis, characterization, and DFT insights

Developing advanced chemotherapeutic drug delivery systems (DDS) is critical for expanding the therapeutic index and reducing the off-target toxicity of potent anticancer agents. In this study, a novel multifunctional nanocomposite, CS/M/MIL, was engineered by integrating magnetite (M) nanoparticles and chitosan (CS) into a metal-organic framework (MOF), MIL-100(Fe), using a modified hydrothermal method. This platform was utilized to encapsulate the anticancer drug epirubicin (EPR), achieving a remarkably high drug entrapment efficiency (EE) of 89.4%. Physicochemical characterization, including XRD and SEM, confirmed successful composite formation and structural integrity, with the modified CS/M/MIL showing a particle size increase to approximately 400 nm compared to the pristine MOF. Textural analysis revealed a transition from a highly microporous structure (BET surface area: 1804.68 m²/g) to a hierarchical macroporous architecture (50.95 m²/g) following functionalization. In vitro release kinetics demonstrated a pH-responsive behavior, with significantly accelerated drug release in acidic conditions (pH 5.0) simulating the acidic endo/lysosomal compartments. Biological evaluations against MCF-7 breast cancer cells revealed that the EPR-loaded nanocomposite significantly enhanced therapeutic efficacy, yielding an IC₅₀ value of 7.57 µg/mL. Furthermore, flow cytometric analysis confirmed that the system promotes substantial apoptosis (31.66%) and induces G2/M phase cell cycle arrest. The significance and novelty of this work lie in the synergistic integration of magnetic responsiveness, biocompatible polymeric coating, and high-porosity MOF architecture into a single platform. Additionally, density functional theory (DFT) calculations provided unique mechanistic insights, identifying Fe³⁺ coordination and hydrogen bonding as the primary drivers for the high affinity between EPR and the nanocarrier. These findings position CS/M/MIL as a superior, targeted carrier for anthracycline-type drugs, offering a pathway to improved clinical outcomes with reduced systemic side effects.