MSN Templated with L-Dopa Amide Derivatives Outperforms the Efficiency of Free-L-Dopa in Reducing Parkinson’s Behavioral Dysfunction in Mice

Mónica Onrubia-Márquez,1 Miguel M Garcia,2– 4 Francisco Navas,1 Samuel Martínez-Erro,1 Antonio Martín,1 Victoria Morales,1 Justine Delaval,5 Lara Merchán-Sánchez,6 Eva Mª Sánchez-Robles,2– 4 Nancy A Paniagua,2– 4 Carmen Rodríguez-Rivera,2– 4 Raúl Sanz,1,7 Carlos Goicoechea,2– 4 Rafael A García-Muñoz1,7 1Department of Chemical and Environmental Technology, Universidad Rey Juan Carlos, Móstoles, Spain; 2Area of Pharmacology, Nutrition and Bromatology, Department of Basic Health Sciences, Universidad Rey Juan Carlos, Unidad Asociada de I+D+i Al Instituto de Química Médica (IQM) CSIC-URJC, Alcorcón, Spain; 3High Performance Experimental Pharmacology Research Group, Universidad Rey Juan Carlos (PHARMAKOM), Alcorcón, Spain; 4Grupo Multidisciplinar de Investigación y Tratamiento del Dolor (i+DOL), Alcorcón, Spain; 5École de Biologie Industrielle (EBI), Cergy, France; 6Area of Histology and Pathological Anatomy, Department of Basic Health Sciences, Universidad Rey Juan Carlos, Alcorcón, Spain; 7Instituto de Investigación de Tecnologías para la Sostenibilidad, Universidad Rey Juan Carlos, Móstoles, SpainCorrespondence: Victoria Morales, Email [email protected] Rafael A García-Muñoz, Email [email protected]: Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by motor dysfunction due to the loss of dopaminergic neurons, with an increasing global prevalence estimated to impact 20 million individuals by 2050. The current standard treatment, L-dopa, loses efficacy over time and often induces dyskinesia, highlighting the need for innovative therapeutic strategies with sustained efficacy and fewer side effects.Methods: In this study, we developed mesoporous silica nanoparticles (MSNs) templated with L-dopa amide derivatives, specifically designed as a drug-structure-directing agent (DSDA). This novel templating approach improves L-dopa loading capacity and enhances controlled-release performance. Two MSN formulations were selected for in vivo evaluation in a murine model of PD induced by unilateral injection of 6-hydroxydopamine (6-OHDA) in the striatum.Results: In vitro studies demonstrated that L-dopa derivatives-loaded MSNs lead to a controlled and sustained release of L-dopa DSDA and in vivo assays corroborated this hypothesis. A single intraperitoneal dose of L-dopa-loaded MSNs was able to reduce the spontaneous rotational behavior observed in 6-OHDA damaged mice and outdid free-L-dopa.Conclusion: This novel strategy may represent a promising alternative to conventional treatment, reducing dose frequency and hence minimizing L-dopa side effects. The results herein emphasize the potential of MSN-based drug delivery systems for PD, providing a basis for future translational research of nanotechnology-based formulations for neurodegenerative disorders. Keywords: Parkinson disease, mesoporous silica nanoparticles, modified L-Dopa, drug-structure-directing agents, drug release systems