Ultrasound-Responsive Folate-Chlorogenic Acid Nanocarrier Targeting Mixed Lineage Kinase 1 for Enhanced Wilms Tumor Therapy.

BACKGROUND

Wilms tumor (nephroblastoma) is the most frequent malignant tumor of the urinary system in children; however, current treatment choices are restricted due to inadequate drug targeting, systemic toxicity, and multidrug resistance. Chlorogenic acid (CGA), a natural polyphenolic molecule, has promise as an anti-Wilms tumor action but has limited water solubility and bioavailability. To address these constraints, the authors created an ultrasound-responsive folate-CGA nanocarrier (1,2-distearoyl-sn-glycero-3-phosphoethanolamine-polyethylene glycol-folic acid-CGA [DSPE-PEG-FA/CGA]) that enables targeted and regulated drug administration.

METHODS AND

RESULTS

The nanocarrier was created utilizing DSPE as the structural backbone, with PEG modification for increased stability and FA conjugation for tumor-specific targeting. Following low-intensity ultrasonic treatment, the nanocarrier increased permeability and induced CGA release via acoustic cavitation effects, greatly enhancing local drug accumulation inside tumor tissues.Ultrasound Augmentation:Comprehensive characterization demonstrated good encapsulation efficiency, consistent particle size, and acceptable ultrasonic responsiveness. In vitro experiments indicated increased cellular absorption via folate receptor-mediated endocytosis and ultrasound stimulation, leading to more cytotoxicity against Wilms tumor cells than nonultrasound-treated controls. In vivo, the DSPE-PEG-FA/CGA system demonstrated selective tumor accumulation, dose-dependent tumor growth suppression, and good biosafety in nude mice, with no changes in body weight or organ damage. Mechanistic research revealed mixed-lineage kinase 1 (MLK1) as a direct molecular target of CGA, since it binds to MLK1's active pocket (specifically residues L303, I228, and A249) and modifies the MAPK and PI3K-Akt signaling pathways to induce apoptosis and decrease proliferation.

CONCLUSIONS

Overall, this work shows that ultrasound-responsive folate-CGA nanotherapy is an effective, safe, and focused method for treating Wilms tumors by combining molecular suppression of MLK1 with ultrasound-enhanced delivery accuracy.