Rodriguez-Nogales, C. (Carlos)
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- Nanomedicines for Pediatric Cancers(ACS, 2018) Aldaz, A. (Azucena); González-Fernández, Y. (Yolanda); Blanco-Prieto, M.J. (María José); Couvreur, P. (Patrick); Rodriguez-Nogales, C. (Carlos)Chemotherapy protocols for childhood cancers are still problematic due to the high toxicity associated with chemotherapeutic agents and incorrect dosing regimens extrapolated from adults. Nanotechnology has demonstrated significant ability to reduce toxicity of anticancer compounds. Improvement in the therapeutic index of cytostatic drugs makes this strategy an alternative to common chemotherapy in adults. However, the lack of nanomedicines specifically for pediatric cancer care raises a medical conundrum. This review highlights the current state and progress of nanomedicine in pediatric cancer and discusses the real clinical challenges and opportunities.
- Brain aging and Parkinson's disease: new therapeutic approaches using drugs delivery systems(Elsevier, 2015) Carmona-Abellán, M.M. (María del Mar); Blanco-Prieto, M.J. (María José); Garbayo, E; Luquin, M.R. (María Rosario); Rodriguez-Nogales, C. (Carlos)ABSTRACT The etiology and pathogenesis of Parkinson’s disease (PD) is unknown, aging being the strongest risk factor for brain degeneration. Understanding PD pathogenesis and how aging increases the risk of disease would aid the development of therapies able to slow or prevent the progression of this neurodegenerative disorder. In this review we provide an overview of the most promising therapeutic targets and strategies to delay the loss of dopaminergic neurons observed both in PD and aging. Among them, handling alphasynuclein toxicity, enhancing proteasome and lysosome clearance, ameliorating mitochondrial disruptions and modifying the glial environment are so far the most promising candidates. These new and conventional drugs may present problems related to their labile nature and to the difficulties in reaching the brain. Thus, we highlight the latest types of drug delivery system (DDS)-based strategies for PD treatment, including DDS for local and systemic drug delivery. Finally, the ongoing challenges for the discovery of new targets and the opportunities for DDS-based therapies to improve and efficacious PD therapy will be discussed.
- Decoration of squalenoyl-gemcitabine nanoparticles with squalenyl-hydroxybisphosphonate for the treatment of bone tumors(Wiley, 2021-12-14) Sebastian, V. (Víctor); Blanco-Prieto, M.J. (María José); Desmaële, D. (Didier); Couvreur, P. (Patrick); Rodriguez-Nogales, C. (Carlos)Therapeutic perspectives of bone tumors such as osteosarcom are main restricted due to the inefficacy of current treatments. We propose here the construction of a novel anticancers qualene-based nanomedicine with bone affinity and retention capacity. A squalenyl-hydroxybisphosphonate molecule was synthetized by chemical conjugation of a 1-hydroxyl-1,1-bi-sphosphonatemoiety to the squalenechain. This amphiphilic compound was inserted onto squalenoyl-gemcitabinenano-particles using the nanoprecipitation method. The co-assemblyled to nanoconstructsof 75 nm, with different morphology and colloidal properties. The presence of squalenyl-hydroxybi-sphosphonate enhanced the nanoparticles binding affinity for hydroxyapatite,a mineral present in the bone. Moreover, the in vitro anticancer activity was preserved when tested in commercial and patient-treated derived pedia tricoste osarcomacells. Furtherin vivo studies will shed lighton the potential of these nano medicines for the treatment of bones arcomas.
- Combinatorial Nanomedicine Made of Squalenoyl-Gemcitabine and Edelfosine for the Treatment of Osteosarcoma(2020) Blanco-Prieto, M.J. (María José); Desmaële, D. (Didier); Moreno, H. (Haritz); Couvreur, P. (Patrick); Lecanda, F. (Fernando); Rodriguez-Nogales, C. (Carlos); Zandueta, C. (Carolina)Due to chemoresistance and a high propensity to formlungmetastasis, survival ratesin pediatric osteosarcoma (OS) are poor. With the aim to improve anticancer activity in pediatric OS, a multidrug nanomedicine was designed using the alkyl-lysophospholipid edelfosine (EF) co-assembled with squalenoyl–gemcitabine (SQ–Gem) to form nanoassemblies (NAs) of 50 nm. SQ–Gem/EF NAs modified the total Gem pool exposure in the blood stream in comparison with SQ–Gem NAs, which correlated with a better tolerability and a lower toxicity profile after multiple intravenous administrations in mice. For in vivo preclinical assessment in an orthotopic OS tumor model, P1.15 OS cells were intratibially injected in athymic nude mice. SQ–Gem/EF NAs considerably decreased the primary tumor growth kinetics and reduced the number of lung metastases. Our findings support the candidature of this anticancer nanomedicine as a potential pediatric OS therapy
- 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.
- 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.
- Combinatorial nanomedicine made of squalenoyl-gemcitabine and edelfosine for the treatment of pediatric cancer(2020-04-27) Rodriguez-Nogales, C. (Carlos); Blanco-Prieto, M.J. (María José); Couvreur, P. (Patrick)Chemotherapy protocols for childhood cancers are still problematic due to the high toxicity associated with chemotherapeutic agents, and incorrect dosing regimens extrapolated from adults. Nanotechnology has demonstrated significant ability to reduce toxicity of anticancer compounds. Improvement in the therapeutic index of cytostatic drugs, makes this strategy an alternative to common chemotherapy in adults. Among anticancer nanomedicines, squalenoyl nanocomposites have obtained encouraging outcomes in a great variety of tumors. The prodrug squalenoyl-gemcitabine was chosen in this study to construct a novel multidrug nanosystem in combination with edelfosine, an alkyl-lysophopholipid with proven anticancer activity. Given their amphiphilic nature, it was hypothesized that both anticancer compounds, with complementary molecular targets, could lead to the formation of a new multitherapy nanomedicine. Nanoassemblies were formulated by nanoprecipitation method and characterized by dynamic light scattering, transmission electron microscopy, X-ray photoelectron spectroscopy and UHPLC tandem mass spectroscopy. It was observed that these molecules spontaneously self-assembled as stable and monodisperse nanoassemblies of 51 ± 1 nm in a surfactant/polymer free-aqueous suspension. Compared to squalenoyl-gemcitabine nanoassemblies, the combination of squalenoyl-gemcitabine with edelfosine resulted in smaller particle size and a new supramolecular conformation, with higher stability and drug content. On the other hand, squalenoyl-gemcitabine/edelfosine nanoassemblies were found to be capable of intracellular translocation in patient-derived metastatic pediatric osteosarcoma cells (531M) and showed a better antitumor profile in vitro than squalenoyl-gemcitabine nanoassemblies in neuroblastoma (SH-SY5Y) and pediatric osteosarcoma (U2-OS) cell lines. The intravenous administration of this combinatorial nanomedicine in mice exhibited a controlled release behavior of gemcitabine and diminished edelfosine plasma peak concentrations. For their in vivo pre-clinical assessment in an orthotopic osteosarcoma tumor model, c-Fos overexpressing P1.15 cells were intratibially injected in athymic nude mice. In comparison with the control groups, the combinatorial nanomedicine was found to decrease the primary tumor growth kinetics and to reduce the number of lung metastases. Our findings support the candidature of squalenoyl-gemcitabine/edelfosine nanoassemblies as a potential pediatric cancer therapy. Improving the quality of life of cancer patients is essential, particularly in the case of the pediatric population. In these studies, we successfully designed squalenoyl-gemcitabine/edelfosine nanoassemblies of 50 nm, which proved to be safe and efficacious in a murine osteosarcoma model. The findings gathered in this thesis shed light on the promising future of combinatory nanomedicine to replace current cancer treatments.