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Gemcitabine and Edelfosine for the Treatment of Pediatric Cancer”

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Gemcitabine and Edelfosine for the Treatment of Pediatric Cancer” Departamento de Tecnología y Química Farmacéuticas Facultad de Farmacia y Nutrición Universidad de Navarra TESIS DOCTORAL “COMBINATORIAL NANOMEDICINE MADE OF SQUALENOYL-GEMCITABINE AND EDELFOSINE FOR THE TREATMENT OF PEDIATRIC CANCER” Carlos Rodríguez Nogales Pamplona, 2020 Departamento de Tecnología y Química Farmacéuticas Facultad de Farmacia y Nutrición Universidad de Navarra TESIS DOCTORAL “COMBINATORIAL NANOMEDICINE MADE OF SQUALENOYL-GEMCITABINE AND EDELFOSINE FOR THE TREATMENT OF PEDIATRIC CANCER” Trabajo presentado por Carlos Rodríguez Nogales para obtener el grado de Doctor Fdo. Carlos Rodríguez Nogales Pamplona, 2020 UNIVERSIDAD DE NAVARRA FACULTAD DE FARMACIA Y NUTRICIÓN Departamento de Tecnología y Química Farmacéuticas DÑA. MARÍA JOSÉ BLANCO PRIETO, Doctora en Farmacia y Catedrática del Departamento de Tecnología y Química Farmacéuticas de la Universidad de Navarra y, D. PATRICK COUVREUR, profesor emérito de la Universidad Paris-Saclay y miembro de la Academia de las Ciencias en Francia, certifican: Que el presente trabajo, titulado “Combinatorial nanomedicine made of squalenoyl-gemcitabine and edelfosine for the treatment of pediatric cancer”, presentado por D. CARLOS RODRÍGUEZ NOGALES, para optar al grado de Doctor en Farmacia, ha sido realizado bajo su dirección en el Departamento de Tecnología y Química Farmacéuticas de la Universidad de Navarra. Considerando finalizado el trabajo autorizan su presentación a fin de que pueda ser juzgado y calificado por el Tribunal correspondiente. Y para que así conste, firma la presente: Fdo: Dra. María José Blanco Prieto Dr. Patrick Couvreur Pamplona, 2020 Esta tesis doctoral se ha llevado a cabo gracias a becas otorgadas para la formación del personal investigador de la Asociación Española Contra el Cáncer (AECC) y la Asociación de familiares y amigos de pacientes con neuroblastoma (NEN, Nico contra el Cáncer). A mis padres, Ángel y Pilar La belleza, Luminoso instante Entre la rutina y la nada Espuma del tiempo. “Estelas” (Instantáneas, de A.L. Rodríguez) AGRADECIMIENTOS Quisiera agradecer de la manera más breve posible a todos aquellos que me han acompañado a lo largo de este trabajo y que han hecho posible su consecución. En primer lugar, me gustaría dar las gracias a la Universidad de Navarra y en particular a la Facultad de Farmacia y Nutrición y al Departamento de Tecnología y Química Farmacéuticas, por haberme permitido realizar esta tesis doctoral. No quisiera olvidarme de la Facultad de Farmacia de la Universidad Complutense de Madrid, donde di los primeros pasos de mi formación. Gracias, también, a la Asociación Española contra el Cáncer (AECC) y a la Asociación de familiares y amigos de pacientes con neuroblastoma (NEN, Nico contra el Cáncer), por darme la oportunidad de aportar mi granito de arena en la lucha contra el cáncer infantil. Gracias Joaquín (Molí) por confiar en mí. Por supuesto doy las gracias a mi directora de tesis, María Blanco, por brindarme la oportunidad de trabajar y crecer profesionalmente junto a ti. Gracias por tu constancia, preocupación y trabajo; pero sobre todo por compartir mis éxitos y fracasos a lo largo de estos años. Gracias también a mi co-director Patrick Couvreur. Travailler avec toi a été un véritable honneur pour moi. Tes connaissances, ton dévouement et ton leadership m’ont inspiré jour après jour et je ne l` oublierai jamais. Merci beaucoup et bonne chance. Me gustaría agradecer profundamente a las personas que han participado en este proyecto de investigación y han puesto todo su empeño y dedicación para que saliera adelante: Simona Mura (Université Paris-Sud), Silvia Irusta (Universidad de Zaragoza), Haritz Moreno (CIMA), Carolina Zandueta (CIMA), Azucena Aldaz (CUN) y Rosa Noguera (INCLIVA). De manera significativa, quisiera dar las gracias a Víctor Sebastián (Universidad de Zaragoza) por su gran implicación, disposición para ayudar siempre y por sus magníficas fotos de microscopía; a Fernando Lecanda (CIMA), por confiar en nosotros y motivarnos en la última fase de la tesis. Por último, a Didier Desmaële (Université Paris-Sud). Merci beaucoup Didier, de me laisser prendre mes repas avec toi, prendre un café avec toi et faire de la chimie organique avec toi et de ne jamais abandonner et toujours chercher des solutions. Quiero dar las gracias a todos los profesores e investigadores del departamento por vuestra ayuda. Del mismo modo, gracias a los doctorandos galénicos Ana, Jorge, Cristian, Alba; pero también a los del otro ala; Leire, Diego, Nicolás, Itziar y muchos más que me dejo. Muchas gracias Hugo, por decirme siempre lo que piensas, por tu ayuda y afecto dentro y fuera del laboratorio y por donar tus eritrocitos para este trabajo. Por otro lado, quisiera agradecer también el apoyo recibido dentro y fuera del Institut Galien a mis compañeros de la Universidad Paris-Sud y en especial a Arnaud, Federica, Raúl y Flavio. Me gustaría agradecer el apoyo y cariño recibido por mis compañeros y compañeras de equipo Elisa, Edurne I., Yolanda, Simón, Edurne L., Pablo, Souhaila y, especialmente, a Laura por caminar conmigo desde el primer momento hasta el final y compartir los momentos más difíciles. Gracias a los míos aquí: Violeta, Belén, Manuel, Iratxe, Íñigo, Mónica y Maite; por estar siempre a mi lado cuando lo he necesitado. Vio, sé que mi hogar estará siempre donde tú estés. Sin duda, gracias/mila esker a mis compañeros de viaje musical, Mikel y Eneko, por ayudarme a poner banda sonora a esta tesis. Gracias también a todos mis amigos y amigas de Pozuelo de Alarcón, San Lorenzo del Escorial y de Madrid por estar ahí siempre para mí desde la distancia (creo que sois demasiados para citaros aquí). Por último, gracias de todo corazón a mi familia y especialmente, a mi padre Ángel, mi madre Pilar, y mi hermano Jaime, porque sin vosotros esto no hubiera sido posible. Gracias por apoyarme, educarme y quererme como soy. Gracias a mi abuela Pilar, por preguntarme hasta el último instante cuándo regresaría a Madrid. Tuviste que dejarnos en este periodo pero vino Ana, a la que también le doy las gracias por revolucionar y llenar de alegría a nuestra familia. A TODOS, GRACIAS TABLE OF CONTENTS ABBREVIATIONS ..................................................................................................... 1 INTRODUCTION 3 Nanomedicines for pediatric cancers ABSTRACT ..................................................................................................... 6 1. INTRODUCTION ........................................................................................ 7 1.1. Chemotherapeutic toxicity in pediatric cancer .............................. 7 1.2. Physiology-based pharmacokinetic models (PBPK) ..................... 8 1.3. Nanomedicines for pediatric cancers ............................................. 8 2. BLOOD CANCERS ..................................................................................... 10 2.1. Leukemias ...................................................................................... 10 2.2. Hodgkin and non-Hodgkin lymphoma .......................................... 12 2.3. Clinical nanomedicines in blood cancers ...................................... 13 3. CANCERS OF THE CENTRAL NERVOUS SYSTEM ............................. 16 3.1. Nanotechnology and blood-brain-barrier ...................................... 16 3.2. Gliomas .......................................................................................... 17 3.3. Medulloblastoma ........................................................................... 18 4. NON-CENTRAL NERVOUS SYSTEM EMBRYONAL TUMORS ......... 19 4.1. Neuroblastoma ............................................................................... 19 4.2. Retinoblastoma .............................................................................. 20 5. BONE TUMORS AND SOFT TISSUE SARCOMAS ................................ 21 5.1. Osteosarcoma ................................................................................ 21 5.2. Ewing Sarcoma .............................................................................. 23 6. KEY MILESTONES IN PEDIATRIC CANCER NANOMEDICINE ........ 25 7. CONCLUDING REMARKS ....................................................................... 26 ACKNOWLEDGMENTS ................................................................................ 26 REFERENCES ................................................................................................. 27 HYPOTHESIS AND OBJECTIVES ........................................................................ 41 CHAPTER I 45 A unique multidrug nanomedicine made of squalenoyl-gemcitabine and alkyl- lysophospholipid edelfosine ABSTRACT ..................................................................................................... 48 1. INTRODUCTION ........................................................................................ 49 2. MATERIAL AND METHODS.................................................................... 50 2.1. Materials ........................................................................................ 50 2.2. Preparation of nanoassemblies ...................................................... 51 2.3. UHPLC–MS/MS method .............................................................. 51 2.4. Electron microscopy imaging ........................................................ 52 2.5. XPS assays ..................................................................................... 52 2.6. Hemolysis evaluation ...................................................................
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