Repurposing pentamidine using hyaluronic acid-based nanocarriers for skeletal muscle treatment in myotonic dystrophy

• Published in: Nanomedicine 2023-01, Vol.47, p.102623, Article 102623
• Main Authors: Repellin, Mathieu, Carton, Flavia, Boschi, Federico, Galiè, Mirco, Perduca, Massimiliano, Calderan, Laura, Jacquier, Arnaud, Carras, Julien, Schaeffer, Laurent, Briançon, Stéphanie, Lollo, Giovanna, Malatesta, Manuela
• Format: Article
• Language: English
• Subjects: Bioengineering; Biomaterials; C2C12 cells; Cellular Biology; DM1 cell model; Galenic pharmacology; Humans; Hyaluronic Acid; Life Sciences; Muscle, Skeletal; Muscular dystrophies; Myotonic Dystrophy - drug therapy; Myotonic Dystrophy - genetics; Nanoparticles; Pentamidine; Pharmaceutical sciences; Pharmacology
• ISSN: 1549-9634; 1549-9642
• DOI: 10.1016/j.nano.2022.102623

In a context of drug repurposing, pentamidine (PTM), an FDA-approved antiparasitic drug, has been proposed to reverse the splicing defects associated in myotonic dystrophy type 1 (DM1). However, clinical use of PTM is hinder by substantial toxicity, leading to find alternative delivery strategies. In this work we proposed hyaluronic acid-based nanoparticles as a novel encapsulation strategy to efficiently deliver PTM to skeletal muscles cells. In vitro studies on C2C12 myoblasts and myotubes showed an efficient nanoparticles' internalization with minimal toxicity. More interestingly, our findings evidenced for the first time the endosomal escape of hyaluronic acid-based nanocarriers. Ex vivo studies showed an efficient nanoparticles' internalization within skeletal muscle fibers. Finally, the therapeutic efficacy of PTM-loaded nanosystems to reduce the number of nuclear foci has been demonstrated in a novel DM1 in vitro model. So far, current data demonstrated the potency of hyaluronic acid-based nanosystems as efficient nanocarrier for delivering PTM into skeletal muscle and mitigate DM1 pathology. Illustration of hyaluronic acid-based nanoparticles to deliver pentamidine in C2C12 skeletal muscle myoblasts and myotubes and in explanted skeletal murine muscle to treat DM1 pathology. [Display omitted] •Hyaluronic acid-based nanoparticles were efficiently internalized into muscle cells both in vitro and ex vivo.•CD44 receptors play a key role in the uptake of hyaluronic acid-based nanoparticles.•Novel established DM1 cell model accurately represents theDM1 pathological phenotype.•Pentamidine loaded into nanoparticles highly decreased the number of DM1 nuclear foci.•Pentamidine loaded hyaluronic acid-based nanoparticles offer an innovative strategy for DM1 treatment.