The need for nanocarriers in medicine arises from the increasing number of therapeutic and diagnostic agents whose efficacy is affected by nonspecific cell and tissue biodistribution, systemic and organ toxicity, poor solubility and bioavailability, or rapid metabolization and excretion. Nanogels show advantages over other nanoparticles: improved flexibility and biocompatibility, simple preparation, high water content, high stability and high loading capacity for both hydrophilic and hydrophobic molecules. However, the use of polymeric nanogels presents challenges associated with stimuli-triggered release, biodegradation, polydispersity and batch-to-batch reproducibility in the preparation of polymers. Molecular gels, formed by low molecular weight molecules, may represent an exciting alternative CHAPTER 6. CONCLUSIONS CHAPTER 7. EXPERIMENTAL SECTION ANNEXES ANNEXE I. Resumen en castellano ANNEXE II. Reprint of published papers CHAPTER 1
GENERAL INTRODUCTIONNANOPARTICLES AS CARRIERS 8 menopausal therapy) 51 and Taxol and Taxotere (with paclitaxel and docetaxel, for cancer treatment). 39 Liposomal Nanocarriers. Liposomes are spherical vesicles comprising one or more concentric lipid bilayers, with an aqueous polar core, a lipophilic bilayer compartment and a hydrophilic exterior. 54,55 Hydrophobic ingredients can be inserted into the lipid bilayer or sequestered in the core, whereas water-soluble molecules can be encapsulated in the core. The lipid bilayer is usually composed of phospholipids and sterols such as cholesterol, the latter controlling membrane permeability and fluidity. The physicochemical properties of liposomes are determined by the lipid composition, sterol concentration, surface charge and nanoparticle size. 56 For example, although liposomes enter the cell via endocytic processes, by adhering and fusing with the bilayer of the cell membrane, the overall surface charge tunes the cellular uptake: neutral liposomes do not readily interact with cells and release the content in the extracellular space, whereas positively charged liposomes readily interact with the negative charge on the cell surface via electrostatic forces. 57 Also, the conjugation of hydrophilic polymers, such as PEG, has been used to address the rapid elimination from the bloodstream due to opsonization and clearance by the liver and the spleen, which limits their bioavailability. 58 Ligand-targeted liposomes have also been engineered to promote sitespecific binding. 59 Liposomal nanocarriers can be engineered to respond to temperature and/or pH. 60,61 Due to their biodegradable and biocompatible properties, liposomes undoubtedly represent the most successful type of drug delivery systems to enhance therapeutic potency. Liposome nanocarriers reached the market in 1995 with Doxil, a liposome containing doxorubicin. Since then, ten further products have been approved by the FDA/European Medicines Agency (EMA) for clinical use, mostly for combination cancer therapy. 39 Exceptionally, AmBisome (carrying amphotericin B) is ...