Design and in vitro/in vivo evaluation of a targeted immunotherapy platform for the treatment of melanoma

Résumé

The proposal of this work has been the combination of immunotherapy and chemotherapy, applying the advantages of nanotechnology. To achieve the present aim, several steps represented in the different chapters have been addressed. First, a detailed review about the state of the art of immunoliposomes (ILs), as well as a summary about the main key points that have to be controlled to develop adequate ILs, are reported in Chapter 1. Chapter 2 is focused on the development of different ILs coupled with a specific monoclonal antibody (mAb), the anti-PD-L1 and its Fab’ fragment, using different PEG percentages in the liposome composition and coupling methods, to be, all of them, later assayed in in vitro / in vivo studies. Here, factors such as ligand density and orientation have been optimized, making an important effort to achieve a formulation able to deal with adequate characteristics to reach the tumor area and produce efficient cellular uptake/internalization and immune activity. Finally, in Chapter 3, the formulation selected in the previous work has been combined with Doxorobucin (Dox) as a proof of concept, to evaluate its in vitro / in vivo activity. This immune-nanoplatform encapsulating Dox and targeted against PD-L1 showed a dual mechanism characterized by an immune stimulation and a cytotoxic activity, both contributing to reduce and eliminate cancer cells.