Titolo della tesi: Development of Drug Delivery Systems for ERAP Modulators for the Treatment of Cancer and Autoimmune Diseases
Endoplasmic reticulum (ER) aminopeptidases ERAP1 and ERAP2 play a key-role in antigen presentation by trimming peptides for binding to Major Histocompatibility Complex (MHC) class I molecules and, thus, recognition by immune cells.
Abnormal expression of ERAP or functional genetic variations impair this process, leading to inadequate immune responses and ultimately, contributing to the pathogenesis of cancer and autoimmune diseases.
To improve current therapeutic approaches focused on using small molecule ERAP inhibitors, two polymer-based drug delivery systems (DDS) were developed, with the aim of enhancing the safety and efficacy of the compounds by promoting a controlled and targeted release and minimizing the occurrence of unwanted side effects.
ERAP1 inhibitors were encapsulated in Poly(ethylene glycol)-block-Poly(L-Histidine) - PEO-b-PHis nanoparticles, exploiting the pH-responsiveness of the PHis block for targeted release at acidic pH, similar to that present in the tumor microenvironment (TME). When encapsulated into nanoparticles, ERAP1 inhibitors reduced the stability and expression of non-classical MHC class I molecules. Moreover, cell viability assays confirmed the non-toxicity of DDS, even when the inhibitor was administrated at high concentrations.
ERAP2 inhibitors were encapsulated into polymeric electrospun nanofibers as well. The Poly(vinyl-alcohol)-Liposome - PVA_L formulation demonstrated high encapsulation efficiency and a sustained release profile, maintaining the integrity and therapeutic concentrations of ERAP2 inhibitors. Furthermore, these nanofibers loaded with ERAP2 inhibitors disrupted antigen presentation and showed no toxicity at various concentrations in the cellular environment.
Overall, the designed polymer-based DDS have been shown to release ERAP inhibitors in a controlled and targeted manner, to reduce non-classical MHC class I expression and antigen presentation, and most important to exhibit no-cytotoxic effects at the cellular level, making them promising candidates for clinical applications in the treatment of cancer and autoimmune diseases.