Síntesis de nanoestructuras biopoliméricas para aplicaciones biomédicas

Résumé

One of the biggest challenges facing modern medicine is to find effective treatments for complex diseases and to improve the quality of life for patients suffering from them. One of these diseases is cancer which, according to data from the World Health Organization, caused almost 10 million deaths during the year 2020. Effective drugs have been developed for decades, but they have several disadvantages, mainly their toxic effect on healthy cells and their low bioavailability. This significantly reduces patients' quality of life and the effectiveness of treatments. For this reason, during the last years, selective drug transport mechanisms have been studied to minimize side effects and promote therapeutic action on cancer cells without significant effect on healthy tissues. The use of nanotechnology has generated relevant benefits in medical-related fields. Nanoscale structures allow drugs to be loaded and targeted to specific tissues, enabling controlled release, reducing toxicity and increasing efficacy. At the cellular level, the behavior of nanoparticles depends on many factors, but particle size (less than 200 nm) and size distribution are among the most important characteristics that will determine biological fate, toxicity and in vivo distribution. Additionally, the global increase in epidemics and mortality rates associated with multidrug-resistant bacteria has made combating infectious diseases a global concern. Bacterial resistance to antibiotics is a major problem, as some infections become untreatable and cause numerous deaths worldwide. Consequently, there is an urgent search for effective antibacterial agents with new mechanisms to treat infections. Similarly to cancer treatment, nanotechnology, and especially nanoparticles, may offer good alternatives to antibiotics. However, the details of the antibacterial mechanisms of nanoparticles are not yet fully understood. Until now, several materials have been used to synthesize nanoparticles including lipids, natural or synthetic polymers or inorganic materials. In recent years, research interests have focused on the use of biopolymers, which are known to be highly biocompatible, biodegradable and innocuous while they have shown to be suitable for encapsulating a wide variety of drugs. Among all the biopolymers available, silk fibroin, cellulose and chitosan are those that have been used in this thesis. Silk fibroin has a high capacity for loading, transporting and delivering a wide range of bioactive molecules, making it an excellent material for drug delivery. In this thesis, two drugs of natural origin (naringenin and rosmarinic acid) and a drug of synthetic origin (ibrutinib) loaded in silk fibroin nanoparticles have been evaluated. The best results in terms of bioactivity of the loaded nanoparticles have been obtained with ibrutinib so these nanoparticles have been subsequently functionalized with folic acid to be able to direct them specifically to tumor cells, which overexpress the folate receptor, and, in this way, to reduce or to eliminate side effects on healthy cells. On the other hand, cellulose is also a biopolymer with excellent properties to be used as a drug carrier. In this work, cellulose nanoparticles have also been synthesized from microcrystalline cellulose solutions in ionic liquid with an environmentally friendly process. For the first time, the bioactivity of cellulose nanoparticles obtained with this procedure in healthy and tumor cells has been studied with the aim of being able to use them later as a drug vehicle. Finally, chitosan is a biopolymer with antibacterial properties which, along with the antimicrobial potential of gold, allow the design of nanoparticles for the effective treatment of bacterial infections. In this thesis, chitosan-gold nanoparticles with bactericidal action have been synthesized. Chitosan fulfills a double mission: it reduces the starting gold salt and stabilizes the nanoparticles obtained. A simulation model using molecular dynamics has also been developed to evaluate the interaction between chitosan and the bacterial membrane, which has been compared with the results of the bactericidal activity of the nanoparticles experimentally obtained. Therefore, the main objective of this doctoral is to synthesize and characterize biopolymeric nanoparticles for biomedical applications, specifically as carriers of antitumor and antibacterial drugs. The results obtained in this doctoral thesis have contributed to a more detailed understanding of the development and characterization of new nanostructures for biomedical applications in the field of cancer treatment and bacterial infections. Some of these results will certainly contribute to the design of future in vivo studies.