Large-scale manufacturing of radiation sculptured therapeutic nanogels

Nanogels (NGs), or small particles formed by physically or chemically crosslinked polymer networks, represent a niche in the development of “smart” nanoparticles for drug delivery and diagnostics. Yet, they offerunique advantages over other systems, including a large and flexible surface for multivalent bio-conjugation; an internal 3D aqueous environment for incorporation and protection of (bio)molecular drugs; the possibility to entrap light-activemolecules, metal or mineral nanoparticles for imaging or phototherapeutic purposes; stimuli-responsiveness to achieve temporal and/or site control of the release function and biocompatibility. The availability of inexpensive, robust and versatile synthetic methodologies is at the basis of the development of effective nanogel-based theragnostic devices. In particular, we have established that nanogels can be produced with high yields and through-puts by pulsede-beam irradiation of dilute aqueous solutions of water-soluble biocompatible polymers e.g. poly(N-vinyl pyrrolidone), and functional acrylic monomers, such as acrylic acid or (3-aminopropyl) methacrylamide hydrochloride, using industrial electron accelerators and set-ups (see Figure 1). [1-4] Nanogels are the result of chemical follow-up reactions initiated by a continuous series of electron pulse-generated hydroxyl radicals in de-aerated water. A number of radical sites are generated on the polymer chains,which may have a different fate depending onthe system composition and irradiation conditions.Intra-molecular and inter-molecular radical recombination as well as disproportionation, chain scission and monomer or short polymer segments grafting may occur up to different extent. As a result, crosslinked-core nanoparticles with multi-armed surfaces can be generated, with controlled size, crosslinking density, surface electric charge density, number and nature of functional groups.No recourse to organic solvents, toxic initiators or catalysts and surfactants is made, therefore expensive or time-consuming purification procedures are not required. Simultaneous sterilization can be achieved depending on the irradiation doses. Long-term colloidal stability in the formof aqueous dispersions and redispersability from the freeze-dried form are advantageous properties especially in the view of a pharmaceutical use. Nanogels have been decorated with fluorescent probes, peptides, antibodies or oligonucleotides and/or conjugated to both molecular and macromolecular model drugs to demonstrate their amenability to be transformed into bio-hybrid, smart drug nanocarriers. All the base nanogels have been proved to benot cytotoxic or genotoxic at the cellular level. Indeed, they showed a good affinity for cells, as they rapidly and quantitatively bypass the cellularcompartments, to accumulate in specific cell portions for the first hours, to bethen completely released from the cells after 24 h.[5] In particular, active targeting features toward specific cell types and smart delivery functions of model chemotherapeutics of purposely designed bio-hybrid nanogels will be presented.