Development of new intelligent nano-systems for the treatment of cardiovascular diseases and cancer

The aim of the present PhD project was the design, synthesis and characterization of two different kinds of nanoparticles: i) new acrylate terpolymer-based nanoparticles (PBMA-(PEG)MEMA-PDMAEMA) and ii) inter polymeric complex-based nanoparticles (PMAA-PVP) for the release of drugs to a specific pathological area of the body. Nanoparticles were obtained both in the form of nanospheres (nanoparticles with a dense polymeric matrix) and nanocapsules (nanoparticles with a hollow structure) with the aim of maximizing the amount of encapsulated and release drug. Secondly, the ability of the nanoparticles to load and then release a nucleic acid (DNA) and a synthetic nucleoside (AZA), to be used in cancer or cardiovascular diseases treatment was evaluated. Moreover, NPs were covalently functionalized in order to obtain active targeting toward cancer cells by using folic acid as ligand. Molecularly imprinted technique was also taken into account as an alternative method to chemical coupling in order to obtain active targeting toward a specific pathological area. Finally, PCL micro fibers functionalized with AZA-loaded PMAA-PVP-based NPs were produced to obtain a combined system for the delivery of a cardioinductive agent in infarcted myocardium. All the samples were characterized from a morphological, physicochemical, functional and biological point of view. In addition, cell uptake tests were carried out in order to verify the obtainment of active targeting towards cells overexpressing folic acid receptors. SEM analysis showed a spherical shape, nanometric dimensions and homogeneous distribution of the nanoparticles for both systems, also confirmed by DLS measurements. FT-IR Chemical Imaging analysis carried out on the nanocapsules before and after removal of the core, highlighted the presence of the cavity. HPLC analysis pointed out a good encapsulation efficiency of both DNA and AZA for both systems of nanospheres and nanocapsules, with a tendency of a maximization of the amount of the absorbed active principle in the case of nanocapsules. The effects of the cavity was also evident on the release kinetics for both systems, leading to a more controlled and sustained release in comparison to nanospheres. Chromatographic analysis also pointed out the molecular recognition ability of molecularly imprinted nanoparticles, with a recognition factor much higher than 1 for both kinds of systems, suggesting the formation of recognition sites. In vitro MTT test showed that both kinds of nanospheres and nanocapsules before and after covalent functionalization did not have cytotoxic effects on the cells. Finally, PCL-based microfibers containing AZA-loaded NPs highlighted a more controlled and sustained release of the synthetic nucleoside if compared with the release from free nanoparticles. In conclusion, the investigation carried out in this study showed that both terpolymer and PMAA-PVP-based nanoparticles could be good candidates to be used as novel delivery systems of nucleotides and nucleosides for possible applications in cancer and cardiovascular disease treatment