SYNTHESIS AND DESIGN OF POLY(AMIDOAMINE)S WITH TAILORED PROPERTIES FOR BIOMEDICAL APPLICATIONS

This PhD thesis deals with the straightforward synthesis of polyamidoamine (PAA) biomaterials and their chemical, physicochemical and biological characterization. The scope of this research work is dual. First of all, the development of new synthetic approaches for the synthesis of PAAs with controlled molecular architecture and properties. Along this line, heterodifunctional dimers (HDDs), able to give via self-polyaddition PAAs of controlled average molecular weight and mono-functionalized at one end chain, were synthesized and well characterized from a chemical point of view. Hyperbranched polyamidoamines were also synthesized by using an a2, b2, b4 system, in order to establish the feasibility of the branching reaction, avoiding cross-linking, according to the Flory-Stockmayer theory. On the other hand, new polyamidoamine-based biomaterials for different biomedical applications were synthesized and characterized from the biological standpoint as well. In particular, a series of nanoparticles with low IC50 values suitable for the delivery of proteins and genes have been prepared from oppositely charged polymers using a layer-by-layer approach. Their physical size, charge and internal mobility have been characterized as a function of polymer type, composition and number of layers. This study demonstrates that the preparation of stable dispersions of such particles is feasible, and from a small number of building blocks, a wide range of particles is accessible. Hence, the insight derived from these results will have a wider implication for the rational design of such particles in the future. Polyamidoamine-protein conjugate was synthesized to target antimalarial drugs into infected erythrocytes. In this case the strategy was to exploit the properties of a polyamidoamine, namely ISA23, to co-localize with parasite inside infected red blood cells (iRBCs) and the drug transporting ability of bovine serum albumin (BSA) in order to obtain a nanosized copolymer able to bind antimalarial drugs and release them preferentially into iRBCs. The copolymer first proved able to efficiently bind antimalarial drugs forming stable complexes at equilibrium. In vivo and in vitro results have shown a good targeting effect of this drug delivery system, affording to healing of 100% of treated mice. Finally, biodegradable polyamidoamine hydrogels with suitable mechanical and physicochemical properties were synthesized as scaffolds for in vitro culturing of peripheral nervous cells and potential conduits for in vivo nerve regeneration. They proved capable of allowing Schwann (SC) and dorsal root ganglia (DRG) cells adhesion and proliferation