El-Moukhtari, S.H. (Souhaila H.)
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- Nanomedicines and cell-based therapies for embryonal tumors of the nervous system(Elsevier, 2022) Fernández-Teijeiro, A. (Ana); Blanco-Prieto, M.J. (María José); El-Moukhtari, S.H. (Souhaila H.); Garbayo, E. (Elisa); Couvreur, P. (Patrick); Rodriguez-Nogales, C. (Carlos)Embryonal tumors of the nervous system are neoplasms predominantly affecting the pediatric population. Among the most common and aggressive ones are neuroblastoma (NB) and medulloblastoma (MB). NB is a sympathetic nervous system tumor, which is the most frequent extracranial solid pediatric cancer, usually detected in children under two. MB originates in the cerebellum and is one of the most lethal brain tumors in early childhood. Their tumorigenesis presents some similarities and both tumors often have treatment resistances and poor prognosis. High-risk (HR) patients require high dose chemotherapy cocktails associated with acute and long-term toxicities. Nanomedicine and cell therapy arise as potential solutions to improve the prognosis and quality of life of children suffering from these tumors. Indeed, nanomedicines have been demonstrated to efficiently reduce drug toxicity and improve drug efficacy. Moreover, these systems have been extensively studied in cancer research over the last few decades and an increasing number of anticancer nanocarriers for adult cancer treatment has reached the clinic. Among cell-based strategies, the clinically most advanced approach is chimeric-antigen receptor (CAR) T therapy for both pathologies, which is currently under investigation in phase I/II clinical trials. However, pediatric drug research is especially hampered due not only to ethical issues but also to the lack of efficient pre-clinical models and the inadequate design of clinical trials. This review provides an update on progress in the treatment of the main embryonal tumors of the nervous system using nanotechnology and cell-based therapies and discusses key issues behind the gap between preclinical studies and clinical trials in this specific area. Some directions to improve their translation into clinical practice and foster their development are also provided.
- In vivo biodistribution of edelfosine-loaded lipid nanoparticles radiolabeled with Technetium-99 m: Comparison of administration routes in mice(Elsevier, 2022) Bouziotis, P. (Penelope); Blanco-Prieto, M.J. (María José); Xanthopoulos, S. (Stavros); El-Moukhtari, S.H. (Souhaila H.); Tsotakos, T. (Theodoros); Lasa-Saracibar, B. (Beatriz); Loudos, G. (Georges)Edelfosine (ET) is a potent antitumor agent but causes severe side effects that have limited its use in clinical practice. For this reason, nanoencapsulation in lipid nanoparticles (LNs) is advantageous as it protects from ET side-effects. Interestingly, previous studies showed the efficacy of LNs containing ET in various types of tumor. In this paper, biodistribution studies of nanoencapsulated ET, administered by three routes (oral, intravenous (IV) and intraperitoneal (IP)), were tested in order to select the optimal route of administration. To do this, ET-LNs were labeled with Technetium-99 m (99mTc) and administered by the oral, IV and IP route in mice. IV admin- istration of the radiolabeled LNs led to fast elimination from the blood circulation and increased accumulation in reticulo-endothelial (RES) organs, while their oral administration could not provide any evidence on their bio- distribution since large radiocomplexes were formed in the presence of gastrointestinal fluids. However, when the LNs were administered by the IP route they could access the systemic circulation and provided more constant blood ET-LN levels compared to the IV route. These findings suggest that the IP route can be used to sustain the level of drug in the blood and avoid accumulation in RES organs.
- Biosafety evaluation of etoposide lipid nanomedicines in C. elegans(Springer Nature, 2024) Blanco-Prieto, M.J. (María José); El-Moukhtari, S.H. (Souhaila H.); Campo, R. (Ruben) del; Laromaine, A. (Anna); Muñoz‑Juan, A. (Amanda)Neuroblastoma is a pediatric tumor that originates during embryonic development and progresses into aggressive tumors, primarily affecting children under two years old. Many patients are diagnosed as high-risk and undergo chemotherapy, often leading to short- and long-term toxicities. Nanomedicine offers a promising solution to enhance drug efficacy and improve physical properties. In this study, lipid-based nanomedicines were developed with an average size of 140 nm, achieving a high encapsulation efficiency of over 90% for the anticancer drug etoposide. Then, cytotoxicity and apoptosis-inducing effects of these etoposide nanomedicines were assessed in vitro using human cell lines, both cancerous and non-cancerous. The results demonstrated that etoposide nanomedicines exhibited high toxicity and selectively induced apoptosis only in cancerous cells.Next, the biosafety of these nanomedicines in C. elegans, a model organism, was evaluated by measuring survival, body size, and the effect on dividing cells. The findings showed that the nanomedicines had a safer profile than the free etoposide in this model. Notably, nanomedicines exerted etoposide's antiproliferative effect only in highly proliferative germline cells. Therefore, the developed nanomedicines hold promise as safe drug delivery systems for etoposide, potentially leading to an improved therapeutic index for neuroblastoma treatment.
- Oral lipid nanomedicines: Current status and future perspectives in cancer treatment(Elsevier, 2021) Blanco-Prieto, M.J. (María José); El-Moukhtari, S.H. (Souhaila H.); Rodriguez-Nogales, C. (Carlos)Oral anticancer drugs have earned a seat at the table, as the need for homecare treatment in oncology has increased. Interest in this field is growing as a result of their proven efficacy, lower costs and positive patient uptake. However, the gastrointestinal barrier is still the main obstacle to surmount in chemother- apeutic oral delivery. Anticancer nanomedicines have been proposed to solve this quandary. Among these, lipid nanoparticles are described to be efficiently absorbed while protecting drugs from early degradation in hostile environments. Their intestinal lymphatic tropism or mucoadhesive/penetrative properties give them unique characteristics for oral administration. Considering that chronic cancer cases are increasing over time, it is important to be able to provide treatments with low toxicity and low prices. The challenges, opportunities and therapeutic perspectives of lipid nanoparticles in this area will be dis- cussed in this review, taking into consideration the pre-clinical and clinical progress made in the last decade.
- Nanomedicines for the Treatment of Pediatric Neuroblastoma(Universidad de Navarra, 2023-11-09) El-Moukhtari, S.H. (Souhaila H.); Blanco-Prieto, M.J. (María José); Couvreur, P. (Patrick)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.