Porosity Modification in MOF Nanocarriers for pH-Responsive Drug Delivery in Cancer Therapy
Amir Kazemi, Hooman Aghamirza Moghim Aliabadi, Mohammad Hossein Afshari, Mohsen Tamtaji, Hasan Baesmat, Saber Keshavarz, Fateme Zeinali, Elahe Torabi, Ghodsiyeh Sadat Ferdowsi, Faranak Manteghi, Sohrab Rohani, William A. Goddard
Abstract
Metal-organic frameworks (MOFs) have emerged as promising nanocarriers for targeted drug delivery, particularly in cancer therapy. Introducing structural defects into MOFs significantly enhances their drug-loading capacity and release efficiency. This study explores porosity modification through defect-engineered MOF-808 nanocarriers, synthesized via a mixed-ligand strategy, to enhance the stability, pH-responsiveness, and drug delivery efficiency for cancer therapy. The modified MOF-808 variants were loaded with 5-fluorouracil (5-FU) in ethanol and water to optimize the drug loading capacity (DLC) and drug release efficiency (DLE). Among them, MOF-808-15% demonstrated a drug release of 57.7% at pH 7.4 and 70.8% at pH 5.5, showing a 22.7% increase under acidic conditions, which is ideal for pH-responsive drug delivery. Density functional theory (DFT) calculations revealed a strong adsorption energy (-1.13 eV) between MOF-808 and 5-FU, confirming effective drug-framework interactions. Additionally, a biodegradable polydopamine (PDA) coating enhanced the stability and enabled controlled drug release in acidic environments. In the 5-FU@MOF-808-15%/PDA system, 64.4% of the drug was released at pH 5.5, marking a 21.97% improvement compared with neutral conditions. Cytotoxicity assays on MCF-7 cells showed 77.65% inhibition, comparable to free 5-FU (80.4%) at 400 μg/mL. These findings demonstrate that precise defect engineering in MOFs can yield highly efficient and biocompatible drug nanocarriers, paving the way for advanced controlled-release cancer therapies.