Nanomedicines for the Treatment of Pediatric Neuroblastoma

Resumen

Pediatric cancer is still a major challenge to our society. In Spain, more than 1000 cases are diagnosed each year. While there has been clear progress in survival rates over the last 50 years, therapeutic protocols for childhood cancers still face issues related to high toxicity and incorrect dosing regimens. In this context, nanotechnology has shown significant ability to reduce the toxicity of anticancer compounds. Improving the therapeutic index of cytostatic drugs makes this approach an alternative to conventional chemotherapy. However, the lack of nanomedicines specifically designed for pediatric cancer underscore the urgent need to ensure the proper translation of nanomedicines for children. Among pediatric cancers, embryonal nervous system tumors such as neuroblastoma arise due to disruption of normal early developmental pathways and develop in very young children, usually under 2 years old. This disease only affects around 100 children each year, making it a rare disease. Neuroblastoma exhibit significant genetic heterogeneity and varying clinical outcomes. Nevertheless, some genetic abnormalities, such as MYCN amplification, are found in 30% of cases and are associated with high-risk neuroblastoma and poorer prognosis. For these patients, common treatments are still inefficient or lead to severe long-term consequences that affect these children at adulthood. Additionally, other factors, including the tumor microenvironment, can significantly influence tumor aggressiveness, impacting treatment responses and patient survival. In this context, the use of lipid nanoparticles, which are considered safe, scalable, easy to produce and suitable for oral administration present an interesting approach to enhance the therapeutic outlook of neuroblastoma patients. This project was centered on the use of very small size particles made of solid lipids (100-200 nanometers) that act as platforms for delivering the antitumor drug, with the aim of improving its therapeutic index and the quality of life of neuroblastoma patients. The primary objective was to develop new therapeutic nanosystems that can be orally administered and potentially offer effective therapy. This involved the delivery of not only a cytostatic drug currently used for neuroblastoma treatment (etoposide), but also a promising antitumor drug (edelfosine) both combined after their vectorization in lipid nanocarriers. First of all, patient neuroblastoma tumors and samples extracted from high-risk neuroblastoma preclinical models were analyzed showing the role of tumor microenvironment elements in the stiffness of the extracellular matrix. These elements play a major role in aggressiveness and tumor progression. Subsequently lipid nanomedicines were developed and thoroughly characterized. In vitro evaluation in cells revealed that nanomedicines could enhance the drugs effectiveness while sparing non-cancerous cells. This was further corroborated in vivo using Caenorhabditis elegans. These studies provided evidence of the efficacy of the proposed lipid nanomedicines in overcoming the gastrointestinal barrier and reducing the toxicity of etoposide. Further in vivo evaluation in mice demonstrated that nanoencapsulation was a good strategy for the oral administration of anticancer drugs and facilitated lymphatic system engagement. Overall, when tested in a neuroblastoma mouse model, the nanomedicines proved to be an effective strategy that maintained the efficacy of anticancer drugs while significantly reducing toxicities. However, the combination of nanomedicines did not exhibit any improvements in terms of antitumor efficacy when compared to single treatments. Nevertheless, the combination of nanomedicines avoided the emergence of lung metastases when compared to single nanomedicines treatment.