DEVELOPMENT OF INNOVATIVE FORMULATIONS BASED ON POLYSACCHARIDES FOR TUMOR TREATMENT

The development of a wide spectrum of new strategies based on controlled drug delivery systems for tumor treatment have attracted a great deal of interest thanks to their ability to encapsulate and control the release of a large array of anticancer drugs and to their targeting ability to many tumor sites. In the last years, the use of polysaccharides for the development of innovative formulations for drug delivery and targeting is rapidly growing. This could be probably attributed to their peculiar properties, such as biodegradability, biocompatibility, large availability as natural source, low cost manufacturing process and to the presence of multiple reactive groups in their structures, which make them suitable for an easy chemical functionalization. In this context, the overall aim of this thesis was to design, produce and characterize innovative formulations based on polysaccharides with potential application in tumors treatment. In particular, in the present thesis, two different strategies were envisaged. The first one is based on the evidence that chemoattraction through the CXCR4-CXCL12 axis has been shown to be an important mechanism to direct circulating tumor cells toward distant sites. Thus, a fake metastatic niche made up of a gel loaded with CXCL12 was realized. This gel was engineered to create a steep concentration gradient of the chemokine in the proximity of the site of administration/injection thus diverting and capturing the circulating CXCR4+ tumor cells. To this aim, different thermo-responsive gels based on methylcellulose or poloxamers, with or without the polysaccharide hyaluronic acid, were designed, loaded with CXCL12 and their mechanical properties correlated with the ability to attract and capture in vitro CXCR4+ cells. The second strategy concerned the use of polysaccharides both as structural and coating component for different types of nano-carriers, prepared with simple and easily up-scalable manufacturing process. In this context, two different polysaccharides were investigated, hyaluronic acid and enoxaparin. These polysaccharides, thanks to their ability to recognize and bind specific receptors and growth factors overexpressed in tumor cells, can favor a greater drug accumulation to target sites, thus promoting and improving the selectivity and effectiveness of the chemotherapy. The nano-carriers here investigated are chitosan-based polyelectrolyte complexes, poly (lactic-co-glycolic acid) polymeric nanoparticles and self-emulsifying drug delivery systems.