Development of a new class of poly(lipoic acid) nanoparticles as RNA delivery vehicles: the role of the hydrophobic precursors and of the polymeric coating

Lipid nanoparticles have attracted significant interest in the last two decades because of their use as drug carriers for both hydrophobic and hydrophilic therapeutics. In particular they seem to be good candidates to deliver nucleic acids, like mRNA and siRNA, thanks to their biocompatibility and entrapment efficiency. The first goal of this thesis was the synthesis of nanoparticles that are similar to solid lipid nanoparticles (SLNs) in terms of constituents, but with a cross-linked core made of poly-lipoic acid. The aim of this modification was to improve the stability of SLNs, which are based only on hydrophobic interaction. To this aim, a cholesterol derivative coupled with lipoic acid was prepared and successfully tested as precursor for the preparation of the nanoparticles. Encapsulation experiments indicate that polylipoic nanoparticles prepared with this derivative efficiently entrapped siRNA. Subsequently, different polymeric coatings for the poly-lipoic nanoparticles were investigated. Usually, PEG is used as coating polymer because of its stealth properties, but recently it was found that polyoxazolines, such as polymethyloxazoline and polyethyloxazoline, recruits complement proteins triggering capture by immune system cells. This feature could improve the properties of the nanoparticles in vaccine applications. Polymer-functionalized lipids were prepared in this perspective and the tests performed demonstrated that there is a correlation between the coating polymer and the siRNA loading.