Mitochondria-targeted nanoparticles overcome chemoresistance via downregulating BACH1/CD47 axis in ovarian carcinoma

Abstract

The platinum-based chemotherapy is a routine strategy for the treatment of ovarian cancer, while it is prone to chemoresistance in clinical, which hinders the treatment. Therefore, it is urgently needed to elucidate the underlying mechanism of drug resistance and form the appropriate strategy. The sequencing results showed that cisplatin (DDP) resistant ovarian cancer overexpressed BTB and CNC homology 1 (BACH1), and up-regulated the “don't eat me” signal CD47. We identified that hemin, a BACH1 inhibitor, could effectively down-regulate BACH1 and simultaneously inhibit CD47. Moreover, hemin has a synergistic effect with DDP. We designed a pH-responsive nanoparticle (H/D@FA–CaP–NPs) in which folic acid (FA) ensured targeting of ovarian cancer cells, while hemin inhibited BACH1 as well as down-regulated CD47, achieving the promotion of apoptosis of tumor cells and inducing phagocytosis of tumors by macrophages. Moreover, hemin has a synergistic effect with DDP to promote apoptosis of tumor cells. Structurally, hemin and DDP was encapsulated within hydrophobic 1,2-distearoyl-sn‑glycero-3-phospho-ethanolamine (DSPE) to form a tight core, and hydrophilic polyethylene glycol 2000 (PEG2000) and calcium phosphate (CaP) formed the outside shell, and FA was modified on the surface of nanoparticles. In terms of function, (a) FA enhanced the active targeting of nanoparticles to tumors; (b) NPs targeted mitochondria to induce reactive oxygen species (ROS) production; (c) hemin encapsulated in nanoparticles could specifically target BACH1, thereby down regulating CD47; (d) hemin had a synergistic effect with DDP, thus augmenting the chemotherapy. Altogether, mitochondria-targeted nanoparticles H/D@FA–CaP–NPs promoted tumor apoptosis and mobilized phagocytosis to treat tumor, providing a novel scheme for clinical treatment of cisplatin-resistant ovarian carcinoma.