Dottorato in SCIENZE FARMACEUTICHE

Titolo della tesi: Cancer and Antimicrobial Resistance: the role of advanced nanotechnologies

Antibiotic resistance and personalized cancer chemotherapy represent the most important and fascinating public health challenge of the 21st century. The aim of the work described in this thesis is to highlight the interesting physico-chemical characteristics of different nanocarriers, such as: niosomes, liposomes, nanoemulsions and their wide application as innovative delivery systems. Firstly, the focus was put on specific nanocarriers potentially useful for the treatment of cancers, in particular Melanoma, High-grade Serous Ovarian Cancer and Bladder cancer. It was decided to adopt an innovative approach which involves the use of nanocarriers consisting of pH-sensitive substances, like Oleic acid, Cholesteryl hemisuccinate, Tween 80®, Tween 21®, and Tween 85®, able to exploit the differences between the physiological and tumor microenvironment to increase the release of the drug preferentially in the tumor mass. Furthermore, surface modification of nanosystems can improve their target specificity as anticancer drug delivery systems. In this regard, Hyaluronic acid could represent an important option for active targeting by improving drug uptake by tumor cells through the HA-CD44 receptor-mediated endocytosis pathway. On the other hands, the global presence of resistant bacteria is threatening the efficacy of commonly used antibiotics, which is associated with significant morbidity, longer hospitalizations, excessive costs and mortality. Therefore, in the second part of this thesis project, attention was focused on the optimization of drug delivery systems potentially useful for the delivery of Ciprofloxacin, Gentamicin, Rifampicin and two different MmpL3 inhibitors previously identified, BM635 and BM859. Different strategies have been adopted to increase drug targeting and to maximize the efficacy at lower drug dose, such as the formulation of different mucoadhesive drug delivery systems. The characteristics of different polyelectrolytes, like chitosan and ε-poly-L-lysine, have been studied to choose the right strategy to improve specific routes of administration such as pulmonary, nasal and urogenital. An extensive chemical-physical characterization of all samples was carried out evaluating dimensions, ζ-potential, bilayer characteristics such as fluidity, microviscosity and polarity, release capacity of the nanocarriers. Furthermore, stability over time in buffer, simulated biological fluids, and in culture media have been carried out. In collaboration with other research groups, several morphology studies were conducted, by means of Transmission Electron Microscopy, Small-angle X-ray Scattering and Atomic Force Microscopy. Finally, in vitro cellular studies were carried out to evaluate cellular uptake, cytotoxic activity and to verify if the inclusion of compound in the specific nanocarrier could improve its activity.