Nanopartícula polimérica de carboplatina radiomarcada com tecnécio 99m para o imageamento e tratamento do câncer epitelial de ovário

Abstract

Epithelial ovarian cancer (EOC) is the most lethal ovarian malignancy. In early-stage disease, radical surgery can cure most patients. However, approximately 75% of women are diagnosed when the disease has already spread beyond the pelvis, making surgery alone ineffective. In these cases, survival depends on chemotherapy sensitivity. Although most patients initially present platinum-sensitive disease, recurrence is frequent. Additionally, the development of limiting adverse reactions can render treatment unfeasible, negatively impacting both quality of life and therapeutic response. In this context, this study aimed to develop Pluronic F-127 nanomicelles containing carboplatin, radiolabeled with 99mTc, for the imaging and treatment of EOC. The nanomicelles were obtained using the direct dissolution method and characterized by dynamic light scattering and scanning electron microscopy. Release assays, cytotoxicity assessment in SKOV-3 cells, biochemical analysis, pharmacokinetics, and biodistribution studies were also conducted. Characterization revealed spherical nanoparticles with a heterogeneous surface, exhibiting relatively smooth and homogeneous regions, without pronounced irregularities or excessive roughness. These findings suggest that the system possesses good structural stability, with no signs of collapse or significant aggregation, and a slight porosity in some regions, which may influence the controlled drug release. The release profile assay demonstrated a rapid increase in carboplatin release from the nanomicelles within the first hour, followed by a stable and sustained release over more than 20 hours. Cell viability assays indicated that treatment with carboplatin and Pluronic 20% nanomicelles resulted in a low reduction in cell viability at 24 hours. However, the lower IC₅₀ value of the nanomicelles suggests that the Pluronic F-127 formulation enhanced the drug's cytotoxic activity. Notably, after 48 hours, a clear induction of cell death was observed in both compounds, with the lowest IC₅₀ attributed to carboplatin in solution. The convergence of IC₅₀ values at 72 hours suggests that, in the long term, the nanotechnology did not compromise the efficacy of carboplatin, maintaining a cytotoxic effect similar to the free drug. Biochemical analyses revealed variations in hepatic enzyme levels, suggesting protective effects on the liver. However, increased LDH and lipase levels was observed, indicating possible cellular injury and potential pancreatic activity. Pharmacokinetic evaluation demonstrated a half-life of 12.73 hours, longer than that of carboplatin in solution, along with a high volume of distribution and increased clearance. Biodistribution analysis, conducted two hours post-administration, showed significant uptake in the stomach, spleen, right and left kidneys, right and left scrotal sac, and bladder. After 24 hours, a reduction in uptake by the mononuclear phagocytic system was observed, along with increased renal uptake, demonstrating efficient renal elimination. Notably, a significant accumulation in the scrotal sacs was detected at the two-hour mark, which became less prominent after 24 hours. These findings suggest that carboplatin-loaded nanomicelles can mitigate the adverse effects associated with carboplatin, as evidenced by the longer half-life and increased cytotoxic potential at 24 hours, demonstrated by the lower IC₅₀ value.