Aptamer-Functionalized ZIF‑8 Nanomedicine for Targeted Delivery of Gefitinib and siRNA to Treat Tyrosine-Kinase-Inhibitor-Resistant Nonsmall-Cell Lung Cancer

The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor gefitinib (GEF) has been used to treat nonsmall-cell lung cancer (NSCLC); yet, the curative effect of GEF was compromised by drug resistance. Herein, an EGFR aptamer-modified therapeutic strategy (Apt/(siRNA + GEF)@ZIF-8 nanoparticles (NPs)) was fabricated by employing zeolitic imidazolate framework-8 (ZIF-8)-based metal–organic frameworks for targeted delivery of GEF and EGFR siRNA to suppress the drug-resistant gene expression in tumors. Apt/(siRNA + GEF)@ZIF-8 NPs had a high loading efficiency for GEF and siRNA, and the particle size was about 75 nm with a stable crystal structure. In vitro experiments showed that GEF cooperating with siRNA could promote cell apoptosis and displayed a synergistic therapeutic effect on drug-resistant cancer cells. In vivo biodistribution study demonstrated that Apt/(siRNA + GEF)@ZIF-8 could be enriched at tumor sites successfully, which provided a basis for in vivo antitumor experiments. In vivo experiment illustrated that the NPs with good biocompatibility had a high efficiency for conquering the acquired resistance to EGFR tyrosine kinase inhibitors in NSCLC with a tumor inhibition rate of 40.6%. Overall, the findings from this study implied that this biological target nanodrug therapy may provide a promising approach for the treatment of drug-resistant NSCLC.