Formulazione di nanoparticelle di PLGA direzionate attivamente per la veicolazione di pentamidina

Pentamidine (PTM) is an aromatic diamine with antimicrobial effect. Recently, PTM has been proven to enhance myotonic dystrophy physiopathology . However, in this case, the elevated concentrations of PTM required for a noticeable in vivo effect are associated with cellular toxicity, thus hindering its clinical applicability in myotonic dystrophy (DM1) . Nevertheless, the association of PTM to biocompatible and targeted nanocarriers could improve the controlled and selective drug release into muscular cells. On these bases, the aim of the work was the formulation of poly(lactide-co-glycolide) (PLGA) nanoparticles (NPs) loaded with PTM and functionalized with L-carnitine, an active targeting agent that improves the uptake in muscular cells. To this aim, a derivative of L-carnitine, notably stearoyl-L-carnitine (SC), was used, thanks to the ability of the C18-alkyl chain to anchor into the lipophilic inner core of nanoparticles. Nanoparticles were prepared by the nanoprecipitation technique (an easy and scalable production process), using PLGA 75:25, PTM, and SC dissolved into the organic solvent. Aiming at the stability optimization of the NPs, different aqueous phases were tested. To characterise the nanoparticles, mean size, zeta potential, and stability were measured. In addition, drug encapsulation efficiency, release profile and cytotoxicity on muscular cells were analysed. Results showed that the composition of the aqueous phase strongly influences the nanoparticles stability; furthermore, the insertion of the SC lipophilic tail into the nanoparticle matrix competes with the incorporation of PTM, while higher drug encapsulation levels were obtained with untargeted nanoparticles. Next steps will concern the evaluation of the in vitro carnitine targeting ability after incubation with muscular cells. Keywords: PLGA, pentamidine, active targeting, nanoparticles 1.Warf et al., «Pentamidine Reverses the Splicing Defects Associated with Myotonic Dystrophy», PNAS, 2009, 106(44):18551-18556. 2. Neaga et al., «Affinity Capillary Electrophoresis for Identification of Active Drug Candidates in Myotonic Dystrophy Type 1», Anal Bioanal Chem, 2018, 410(18):4495-4507.