Targeted Nanocarriers for synergistic drug delivery to Multiple Myeloma

The aim of this Master Thesis work is to develop targeted nanocarriers for drug delivery acting as a synergistic anticancer therapy in Multiple Myeloma (MM). These drug-loaded nanocarriers, thanks to their surface functionalization, can selectively target cancer cells and be internalized by them, avoiding the high toxicity and other side-effects of conventional antitumor therapies. Two different kinds of nanocarriers have been developed: liposomes and lipid-coated Mesoporous Silica Nanoparticles (MSNs). Liposomes, which are spherical vesicles having at least one lipid bilayer, have been prepared using a thin film hydration method and extrusion, to obtain monodisperse suspensions of unilamellar vesicles (about 100 nm). The highly water-insoluble drug AGI-6780 has been encapsulated into the lipid bilayer of liposomes. The second nanoconstruct consists of a Mesoporous Silica Nanoparticle core coated with a self-assembled lipid bilayer (shell). Mesoporous silica is characterized by a good biocompatibility and a high specific surface area (approximately 1000 m2/g), which enables to load a great amount of drug. The Mesoporous Silica Nanoparticles have been synthetized using a template-assisted sol-gel self-assembly process, obtaining 40-50 nm nanoparticles with a mesoporous structure characterized by cylindrical pores (3-4 nm). Furthermore, both nanocarriers have been functionalized with antibody fragments. For this purpose, anti-CD38 monoclonal antibody was chosen by reason of CD38 receptors overexpression in MM cancer cells. AGI-6780 drug is not lethal for cells itself, but it has a synergistic effect with Carfizomib (CFZ), a common chemotherapy drug to which patients often develop resistance. In this context, it is envisioned to deliver the site-selective targeted nanocarriers with the encapsulated AGI drug to the patient while already administering, in a systemic way, the carfilzomib drug. First experiments in in-vitro cell culture of MM have been carried out to explore the correct dose and timing for the synergistic drug action at the Molecular Biotechnology Center (MBC, University of Turin).