Doxorubicin-loaded perfluoropentane nanodroplets enhance radiofrequency ablation efficacy by relieving tumor hypoxia

Aims Radiofrequency ablation (RFA) is a common treatment for malignant tumors, yet recurrence and metastasis persist a major challenge. The hypoxic microenvironment induced by RFA is a key driver of residual tumor aggressiveness and chemoresistance. This study aims to develop perfluoropentane-based doxorubicin-loaded nanodroplets (DOX-NDs) to overcome these limitations.Materials and methods DOX-NDs were synthesized via thin-film hydration and characterized for morphology, stability, and heat-responsive behavior. In vitro studies examined the mechanisms of hypoxia alleviation, epithelial-mesenchymal transition reversal, and P-glycoprotein downregulation. Antitumor efficacy and biodistribution were evaluated in a 4T1 murine breast cancer model.Results DOX-NDs exhibited uniform spherical morphology and efficient oxygen loading. Upon thermal stimulation (>42°C), a phase transition in the nanodroplets triggered the rapid co-release of doxorubicin and oxygen. This oxygen replenishment promoted HIF-1α degradation, which restored E-cadherin expression and downregulated P-glycoprotein, thereby inhibiting cell motility and reversing chemoresistance. In vivo, the combination of DOX-NDs and RFA significantly suppressed tumor growth and pulmonary metastasis while demonstrating a favorable safety profile.Conclusions Targeting the hypoxia-recurrence axis with an RFA-responsive nanoplatform is a viable strategy. The DOX-NDs successfully integrate chemotherapy with hypoxia modulation, presenting a potential means to improve outcomes following tumor ablation.