Resumen de Multifunctional self-stratified polyurethane-polyurea nanosystems for smart drug delivery
Pau Rocas Alonso
This thesis, entitled ¿Multifunctional Self-stratified Polyurethane-Polyurea Nanosystems for Smart Drug Delivery¿ is structured as a compendium of publications, being organized around a methodological synthetic patent and four internationally peer reviewed publications on the chemical and bio-applicability of the US and EU patented invention. Thus, this manuscript is divided into a General Introduction to drug delivery with polyurethane-polyurea nanosystems and three chapters, which include the publications as Results and Discussion and their introductions as Introduction of each chapter. Chapter 1 is focused on the synthetic methodology to produce a novel kind of self-stratified multifunctional polyurethane-polyurea nanoparticles for cancer nanotherapy. The Introduction of this chapter deals with the key characteristics of drug delivery nanosystems and presents the basis of self-stratification by hydrophobic effects. This chapter contains a methodological patent that breaks down multiple examples of nanoparticles formed by easy-tunable polyurethane-polyurea biocompatible and biodegradable polymers bearing multifunctionalities that are applied to cancer therapy and imaging. In addition, here we include a publication containing the in vitro proof-of-principle of the stratified nature, high encapsulation stability and selective targeting to cancer cells of the nanosystem. Finally, this chapter also contains a publication with the in vivo proof-of-concept for alpha-¿ beta-3 integrin targeted cancer therapy and imaging of polyurethane-polyurea nanoparticles encapsulating plitidepsin as antiangiogenic drug. This research is the consequence of a fruitful collaboration in the framework of a INNPACTO national project (Polysfera, IPT-090000-2010-1) with Dr. P. Calvo, Dr. P. Aviles and Dr. M. J. Guillen in PharmaMar SA; Dr. I. Abasolo, Dr. Y. Fernandez and Dr. S. Schwartz in Vall d¿Hebron Institut de Recerca and Dr. J. Rocas in Ecopol Tech SL. Chapter 2 arises from the encouraging results obtained from Chapter 1 in novel synthetic methods of polymer nanoparticles with shell stratification capacity. The Introduction of this chapter presents the current concerns with titanium implants, the outcome of nanoparticle-coated biomaterials and the perspectives in multifunctional nanomaterials. In this regard, a fantastic collaboration with Dr. C. Mas-Moruno of the BiBiTE group in the UPC lead taking profit of the cell targeting high specificity and great encapsulation capacity of PUUa NPs to develop new generation nanobiomaterials for the enhancement of titanium implants osseointegration and bacterial infection prevention. Titanium implants were innovatively coated by interfacial functionalization with RGD-decorated and roxithromycin-loaded PUUa NPs. This methodology resulted in an outstanding improvement of osteoblastic cells adhesion as well as a dramatic reduction of S. Sanguinis bacteria adhesion onto titanium, which is of great interest to improve the outcome of metallic implants for regenerative medicine. In Chapter 3, we explore another segment of application of PUUa NPs, this is immunotherapy. In collaboration with G. Florez-Canals, Dr. D. Benitez-Ribas and Dr. J. Panes in IDIBAPS and Hospital Clinic of Barcelona we applied PUUa NPs encapsulating budesonide (BDS) corticosteroid for the improvement of BDS efficacy to induce tolerogenicity to dendritic cells (DCs). The Introduction deals with the current therapies used to treat autoimmune diseases as well as recent strategies to target dendritic cells in vivo using smart nanoparticles encapsulating immunosuppressive drugs. Herein we found that when PUUa NPs loaded with BDS were incubated with mature DCs, those differentiated into tolerogenic dendritic cells in a much more efficient manner than DCs incubated with free BDS. As shown in the included publication, levels of costimulatory molecules were enhanced and IL-10 immunosuppressive cytokine was largely secreted. Even more interestingly, fluorescently labeled PUUa NPs proved their DCs targeted behavior in a multi-cellular environment.
