Clinical insight-driven micron-sized cholesterol oxidation platform for membrane lipid therapy of advanced ovarian cancer

Due to the insidious onset of ovarian cancer, the majority of patients are diagnosed at advanced stages, often presenting with extensive pelvic and abdominal metastasis. A significant proportion of these patients exhibit primary or acquired drug resistance, limiting improvements in the five-year survival rate. In this study, an analysis of patient-derived samples demonstrated a strong correlation between cholesterol levels and ovarian cancer progression. Membrane lipid therapy, a strategy that targets the composition, structure, and function of the cell membrane, has demonstrated notable potential in tumor therapy. Subsequently, a novel cholesterol oxidation-mediated membrane lipid therapy employing PLGA microspheres co-loaded with miriplatin (MiR) and cholesterol oxidase (COD) was proposed for drug-resistant advanced ovarian cancer therapy. The microspheres had a particle size of approximately 2.58 μm, with encapsulation efficiencies of 82.98 ± 0.09% for MiR and 32.83 ± 4.30% for COD. In vitro experiments demonstrated that COD-induced cholesterol oxidation modulated the membrane rigidity and fluidity of SKOV3-TR cells, thereby compromising membrane structural integrity and attenuating tumor cell migration. Additionally, the reactive oxygen species generated during cholesterol oxidation disrupted mitochondrial membrane potential and adenosine triphosphate production. The resulting energy deficiency and compromised membrane integrity reduced the expression and function of drug resistance-associated proteins, thereby enhancing chemosensitivity. Moreover, the combined effects of reactive oxygen species and MiR drove resistant cells towards apoptosis. In vivo studies demonstrated that the large-particle PLGA formulation effectively resided in the peritoneal cavity, resulting in superior therapeutic outcomes against drug-resistant metastatic ovarian tumor, as evidenced by fewer peritoneal metastatic nodules and diaphragmatic colonization sites, more extensive tumor tissue destruction, and prolonged survival. More importantly, PLGA encapsulation significantly decreased the toxic side effects associated with continuous platinum-based chemotherapy. Overall, cholesterol oxidation-mediated membrane lipid therapy represented a promising approach for treating advanced ovarian cancer.