• liposomi (liposomes)
• inibitori src (src inhibitors)
• trattamento anticancro (anticancer treatment)
• neuroblastoma
• glioblastoma

Pyrazolo[3,4-d]pyrimidines represent a promising class of compounds capable of inhibiting several oncogenic tyrosine kinases, in particular c-Src, which had become an attractive target for the development of new therapeutic agents against cancer.
The members of this family of compounds were found to induce apoptosis and to reduce proliferation in different cell lines in which c-Src is overexpressed or overactivated, both from solid and hematologic tumors.
The first part of this thesis essentially focuses on the preclinical characterization of compound Si306, a pyrazolo[3,4-d]pyrimidine derivative, identified as a very promising agent for the treatment of glioblastoma multiforme (GBM) and neuroblastoma (NB), two types of cancer arising from nervous system. Si306 and its prodrug pro-Si306 have been demonstrated to inhibit P-glycoprotein, a cellular membrane efflux pump, which is reported to have an important role in multidrug resistance (MDR) for several cancers. Encouraging pharmacokinetic properties and tolerability in vivo were observed for Si306. These findings revealed a novel role of pyrazolo[3,4-d]pyrimidines which may be useful for developing a new effective therapy in MDR cancer treatment, particularly against central nervous system tumors, such as GBM.
In the second section, the development of a stealth liposomal formulation for Si306 for the passive targeting toward NB is described. Si306-loaded liposomes have been prepared with high drug encapsulation efficacy and characterized dimensionally and morphologically by Dynamic Light Scattering (DLS) and Cryo-TEM. Finally, liposomes have been proved to be a long circulating drug delivery system in vivo, capable of enhancing Si306 accumulation in the tumor area thanks to the enhanced permeability and retention effect (EPR).
In the third section, the synthesis and the characterization of a tripeptide with sequence D-Ala-Phe-Lys, which binds a specific reactive site of plasmin, are described. This tripeptide was used to decorate the surface of liposomes encapsulating three selected pyrazolo[3,4-d]pyrimidines, including Si113, a dual c-Src/Sgk1 inhibitor with high anticancer activity against hepatocellular carcinoma (HCC). In vitro
cell uptake and cytotoxicity data in HCC cell line showed that the presence of the tripeptide on the liposomal membrane surface has improved the cell-penetrating ability of liposomes and has increased the activity of two of the three tested compounds.