Screening and enrichment of quercetin from Tetrastigma hemsleyanum Diels & Gilg toward targeted micellar delivery for lung cancer therapy

Background Lung cancer is one of the malignant tumors with the highest mortality in the world. Quercetin (Qu) is a flavonoid compound isolated from Tetrastigma hemsleyanum Diels & Gilg (SYQ), which has multi-target anti-tumor activity. However, there are problems such as low extraction purity, poor water solubility, and difficulty in targeted delivery. Its anti-lung cancer mechanism remains to be elucidated. Objective To investigate the enrichment of Qu by molecularly imprinted polymers (MIPs) and to construct targeted micelles to improve its solubility, tumor targeting, and bioavailability and to explore its anti-lung cancer mechanism by in vitro cell experiments and in vivo animal models. Methods The static adsorption performance of Qu in SYQ extract was evaluated by MIPs. Key targets and pathways were predicted by network pharmacology and molecular docking. The targeted micelles were constructed, and their particle size, morphology, drug loading, and release behavior were characterized. The cytotoxicity and migration inhibition of free Qu and drug-loaded micelles on H1299 and A549 cells were evaluated by MTT assay, crystal violet staining, live/dead cell staining, and scratch healing assay. The uptake efficiency of Qu and the change of intracellular reactive oxygen species level were observed by confocal microscopy. The expression of the PI3K/AKT pathway protein was detected by Western blot, and the H1299 tumor-bearing mouse model was established to evaluate the in vivo distribution and anti-tumor effect. Results Qu was isolated and identified from SYQ extracts using ¹H NMR, MALDI-TOF, Q-TOF LC/MS, and FTIR. When the ratio of Qu to acrylamide was 1:7, the equilibrium adsorption capacity for Qu reached 393.26 μg/g. In network pharmacology, Qu and non-small cell lung cancer (NSCLC) shared 111 common target proteins, with a binding energy of -8.71 kcal/mol between Qu and the BCL-2. The HPP@Qu micelles exhibited a particle size of 107.75 nm, a drug loading capacity of 6.57%, and a cumulative release rate of 55.15% at 72 h. HPP@Qu significantly inhibited the viability and migration of H1299 cells, increased intracellular reactive oxygen species (ROS) levels, downregulated p-PI3K, p-AKT, and BCL-2 proteins, and upregulated cleaved caspase-3. Furthermore, HPP@Qu effectively accumulated in tumor tissues, suppressed tumor growth in tumor-bearing mice, and showed no obvious toxicity to major organs. Conclusion MIPs selectively enrich high-purity Qu from SYQ. Targeted micelles enhance Qu's solubility and tumor targeting, effectively inhibiting tumor growth. Qu induces H1299 cell apoptosis by elevating ROS levels, suppressing the PI3K/AKT pathway, downregulating BCL-2, and activating Caspase-3. These findings reflect the research value of Qu as a potential natural anticancer candidate drug.