Tumor oxygenation nanoliposome synergistic hypoxia-inducible-factor-1 inhibitor enhanced Iodine-125 seed brachytherapy for esophageal cancer

Abstract

Iodine-125 (¹²⁵I) brachytherapy has become one of the most effective palliative treatment options for advanced esophageal cancer. However, resistance toward ¹²⁵I brachytherapy caused by pre-existing tumor hypoxia and hypoxia-inducible factor 1 (HIF-1) signaling pathway activation represents a significant limitation in esophageal cancer treatment. To circumvent these problems, herein, we proposed an innovative strategy to alleviate radioresistance of brachytherapy by co-encapsulating catalase (CAT) and HIF-1 inhibitor-acriflavine (ACF) into the hydrophilic cavities of liposome, termed as "ACF-CAT@Lipo". Under overexpressed H₂O₂ stimulation in the tumor region, the fabricated ACF-CAT@Lipo can generate an amount of O₂ and alleviate tumor hypoxia in vitro and in vivo. Furthermore, cooperating with ACF, the expression of hypoxia-related protein (e.g. HIF-1α, VEGF, MMP-2) are obviously decreased. Importantly, the copious oxygenation and the significant inhibition expression of HIF-1α can further improve the radiosensitivity of ¹²⁵I brachytherapy and finally realize the eradication of esophageal cancer in vivo. The oxygen enrichment and HIF-1 inhibition function of ACF-CAT@Lipo provides a new strategy to overcome the brachytherapy resistance of esophageal cancer therapy.

Keywords: (125)I brachytherapy; Esophageal cancer; HIF-1 functional inhibition; Radiosensitizer; Tumor hypoxia.