Development of novel nanomedicines based on polyurethane-polyurea hybrid nanocapsules for cancer theragnosis

Abstract

[eng] Nanomedicine is one of the cutting-edge fields in most of medical applications, specially, in oncology. The possibility to selectively vehiculize and specifically release a wide range of anticancer compounds gained a lot of attraction in recent years. Besides, the combination of nanomedicine and the use of light is called to be one of the techniques which can extremely increase the selectivity towards tumor lesions removal. Other important challenges in cancer nanomedicine refers to the nanovehiculation of hydrosoluble compounds, promoting their accumulation over tumor tissues and avoiding premature degradation in bloodstream. This Thesis addresses the encapsulation of different bioactive molecules in tumor- targeted polyurethane-polyurea hybrid nanocapsules, towards their use in cancer theragnosis. This research work is clearly focused on the development of less invasive and highly targeted theragnostic techniques in oncology, thus developing and improving possibilities to increase patients’ welfare. The Introduction section includes an intensive revision of the state-of-the-art, both in the nanomedical approach for oncology but also in the use of organic fluorophores and metallodrugs as anticancer agents. The Results and Discussion section is divided into 3 different chapters: The Chapter I presents the nanoencapsulation of different photosensitizers, from organic molecules to metallodrugs complexes, to enhance their phototoxic properties, while avoiding cytotoxic activity under dark conditions of the selected compounds and increasing the phototoxic indexes for an optimal treatment regime. This chapter comprises the nanoencapsulation and biological evaluation of a COUPY derivative, two ruthenium(II)-polypyridyl complexes, a zinc-phthalocyanine compound and the same zinc-phthalocyanine compound conjugated to a cyclometalated iridium(III)-complex. The biological evaluation of encapsulated photosensitizers confirmed the upgrade of biological-performance for all of them, towards an increased selectivity in the use of light within the phototherapeutic-window (650-800 nm). The Chapter II shows how polyurethane-polyurea hybrid nanocapsules can promote cellular uptake of liposoluble iridium(III)-cyclometalated complexes to enable their cytotoxic activity, which is initially hampered by the poor solubility of free compounds in biological media. The results of this chapter expanded the scope about the use of nanoencapsulation for the vehiculation of cytotoxic metallodrugs. Mechanisms that induce cell-death, produced by the treatment with the previously-mentioned iridium(III)- cyclometalated compounds, have been satisfactorily elucidated thanks to the encapsulation in polyurethane-polyurea hybrid nanocapsules, positioning them as a potential instrument in cancer chemotherapy. Finally, the Chapter III of this manuscript addresses the encapsulation of hydrosoluble organic molecules in double-walled polyurethane-polyurea hybrid nanocapsules using a double emulsion synthetic methodology which furnishes water-in-oil-in-water nanocapsules (W/O/W). In particular, the encapsulation of Indocyanine Green, an FDA- approved fluorescent probe, as been carried out towards the development of novel NIR-

operable tools for cancer bioimaging. The proof-of-concept to confirm the specific accumulation of tumor-targeted was successfully carried out in an in vivo melanoma A375 challenged mice model, which clearly demonstrates a promoted tumor accumulation after 9-days of treatment by non-invasive IVIS visualization, using non- toxic and high-penetrating NIR light. This research work sets the stage for the vehiculation of other type of hydrosoluble and less-stable anticancer agents, such as oligonucleotides. In conclusion, this Thesis contributes on the use of polyurethane-polyurea hybrid nanocapsules as novel nanomedical anticancer theragnostic agents for their use in chemotherapy, photodynamic therapy, bioimaging, and fluorescence guided-surgery.

[spa] La nanomedicina es, en la actualidad, uno de los campos más rompedores para diferentes aplicaciones médicas. La posibilidad de vehiculizar selectivamente y liberar de manera específica diferentes compuestos con actividad antitumoral ha suscitado un gran interés durante los últimos años. Esta Tesis aborda la encapsulación de diferentes moléculas bioactivas en nanocapsulas híbridas de poliuretano-poliurea dirigidas a tumor, para su uso como agentes de teragnosis en oncología. Este trabajo de investigación se centra claramente en el desarrollo de técnicas de terapia/diagnóstico menos invasivas y de elevada especificidad en oncología. La sección de Introducción incluye una revisión intensiva del estado del arte, tanto en el enfoque nanomédico para oncología como en el uso de fluoróforos orgánicos, compuestos metálicos y metalofármacos como agentes anticancerígenos. La sección de Resultados y Discusión se divide en 3 capítulos diferentes: El capítulo I presenta la nanoencapsulación de diferentes fotosensibilizadores, desde moléculas orgánicas hasta compuestos metálicos, para potenciar sus propiedades fototóxicas, evitando al mismo tiempo su citotoxicidad en oscuridad, y aumentando los índices fototóxicos para un régimen óptimo de tratamiento. El capítulo II muestra cómo las nanocápsulas híbridas de poliuretano-poliurea pueden incrementar la internalización celular de metalofármacos liposolubles para estimular su actividad citotóxica, que inicialmente se ve dificultada por la escasa solubilidad de los compuestos libres en medios biológicos. Los resultados de este capítulo ampliaron el alcance sobre el uso de la nanoencapsulación para la vehiculización de metalofármacos citotóxicos. Por último, el capítulo III de este manuscrito aborda la encapsulación de moléculas orgánicas hidrosolubles en nanocápsulas híbridas de poliuretano-poliurea de doble pared mediante una metodología sintética de doble emulsión que proporciona nanocápsulas de agua en aceite en agua (W/O/W). En particular, se ha llevado a cabo la encapsulación de una sonda fluorescente aprobada por la FDA, con el fin de desarrollar nuevas herramientas operativas NIR para la bioimagen del cáncer. En conclusión, esta tesis contribuye al uso de nanocápsulas híbridas de poliuretano- poliurea como nuevos agentes nanomédicos de teragnosis del cáncer, para su uso en quimioterapia, terapia fotodinámica, bioimagen y cirugía guiada por fluorescencia.