Miguel Pinto
PE Award 8 – Miguel Pinto
RISE-Health, Faculty of Medicine, University of Porto, Alameda Prof. Hernâni Monteiro, 4200-319, Porto, Portugal.
ORCID
miguel.pinto@med.up.pt
| Using a nanomedicine-based approach as a second chance for tolcapone |
| Pinto Miguel1, Fernandes Carlos1, Machado Cláudia1, Sarmento Bruno2, Remião Fernando3, Otero-Espinar Francisco4 and Borges Fernanda5 1 RISE-Health, Faculty of Medicine, University of Porto, Alameda Prof. Hernâni Monteiro, 4200-319, Porto, Portugal; 2 Instituto de Investigação e Inovação em Saúde (i3S), University of Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal; 3 Associate Laboratory i4HB – Institute for Health and Bioeconomy, Faculty of Pharmacy, University of Porto, R. Jorge de Viterbo Ferreira 228, 4050‐13 Porto, Portugal; 4 Pharmacology, Pharmacy and Pharmaceutical Technology Department, Faculty of Pharmacy and Institute of Materials (iMATUS), University of Santiago de Compostela (USC), 15782 Santiago de Compostela, Spain; 5 RISE-Health, Faculty of Sciences, University of Porto, Rua do Campo Alegre s/n, 4169-007, Porto, Portugal. |
| Abstract Parkinson’s Disease (PD) is a movement disorder characterized by neural degeneration and dopamine depletion. The available therapeutic approaches focus on managing the associated motor symptoms by increasing the dopaminergic pool in the brain. Tolcapone, a catechol-O-methyltransferase (COMT) inhibitor, is one of the most effective adjuvant therapies available for managing PD symptoms. However, its use is problematic due to its hepatotoxic profile and pharmacokinetics, requiring close clinical monitoring and multiple daily dosages [1,2]. Nanomedicine has brought several tools capable of improving a drug’s therapeutic outcome by exploring the unique characteristics of materials at the nanoscale. In this context, the use of nanoparticles as drug delivery systems enables the modulation of the ADMET properties of drugs, potentially improving their therapeutic efficiency [3]. Thus, the aim of the project was the development of tolcapone-loaded nanoparticles to overcome tolcapone’s drawbacks (Figure 1). The first approach was to develop tolcapone-loaded PLGA-based nanoparticles capable of protecting hepatic cells from tolcapone-induced toxicity. After optimization, nanoparticles with sizes around 200 nm were tested in a panoply of hepatotoxicity assays using a human hepatocarcinoma cell line. Nanoparticle formulations proved to decrease tolcapone’s cytotoxicity and to counteract ATP depletion and excessive reactive oxygen species production. Plus, tolcapone-loaded PLGA nanoparticles maintained COMT inhibition capabilities. The second approach was the design of lipid-based carriers to improve the oral bioavailability and blood half-life of tolcapone. Tolcapone-loaded nanostructured lipid carriers (NLCs) up to 120 nm were obtained after optimization. In vitro assays revealed that NLCs have mucoadhesive properties and are stable in biological mimetic conditions. In vitro biological assays demonstrated that NLCs can significantly improve tolcapone permeability across Caco-2 and Caco-2/HT29-MTX cell models, and showed to inhibit COMT. Plus, early in vivo toxicological testing using C. elegans demonstrated survival percentages > 80% after acute exposure in concentrations up to 100 µM. Together, the project presented two nanomedicine-based solutions with the potential to solve tolcapone’s drawbacks, thus giving it a possible second chance for clinical application. |
| References [1] Pinto, M.; Silva, T. B.; et al. Cellular and Mitochondrial Toxicity of Tolcapone, Entacapone, and New Nitrocatechol Derivatives. ACS Pharmacol Transl Sci 2024, 7 (5), 1637–1649. DOI: 10.1021/acsptsci.4c00124 [2] Jorga, K.; Fotteler, B.; et al. Metabolism and excretion of tolcapone, a novel inhibitor of catechol-O-methyltransferase. Br J Clin Pharmacol 1999, 48 (4), 513–520. DOI: 10.1046/j.1365-2125.1999.00036.x [3] Mitchell, M. J.; Billingsley, M. M.; et al. Engineering precision nanoparticles for drug delivery. Nat Rev Drug Discov 2021, 20 (2), 101–124. DOI: 10.1038/s41573-020-0090-8 |