PEGylated PLGA Nanoparticles As a Smart Carrier to Increase the Cellular Uptake of a Coumarin-Based Monoamine Oxidase B Inhibitor
MetadataShow full item record
Despite research efforts to discover new drugs for Parkinson treatment, the majority of candidates fail in preclinical and clinical trials due to inadequate pharmacokinetic properties, namely blood-brain barrier permeability. Within the high demand to introduce new drugs to market, nanotechnology can be used as a solution. Accordingly, PEGylated PLGA nanoparticles (NPs) were used as a smart delivery carrier to solve the suboptimal aqueous solubility, which precludes its use in in vivo assays, of a potent, reversible, and selective monoamine oxidase B inhibitor (IMAO-B) (coumarin C75, IC 50 = 28.89 ± 1.18 nM). Long-term stable PLGA@C75 NPs were obtained by nanoprecipitation method, with sizes around 105 nm and a zeta potential of -10.1 mV. The encapsulation efficacy was around 50%, achieving the final C75 concentration of 807 ± 30 μM in the nanoformulation, which corresponds to a therapeutic concentration 27828-fold higher than its IC 50 value. Coumarin C75 showed cytotoxic effects at 50 μM after 48 and 72 h of exposure in SH-SY5Y, Caco-2, and hCMEC/D3 cell lines. Remarkably, no cytotoxic effects were observed after nanoencapsulation. Furthermore, the data obtained from the P-gp-Glo assay and the cellular uptake studies showed that C75 is a P-glycoprotein (P-gp) substrate having a lower uptake profile in intestinal and brain endothelial cells. Moreover, it was shown that this membrane transporter influences C75 permeability profile in Caco-2 and hCMEC/D3 cells. Interestingly, PLGA NPs inhibited P-gp and were able to cross intestinal and brain membranes allowing the successful transport of C75 through this type of biological barriers. Overall, this work showed that nanotechnology can be used to solve drug discovery related drawbacks. Copyright © 2018 American Chemical Society.
Showing items related by title, author, creator and subject.
Synthesis and structure-activity relationship study of novel 3-heteroarylcoumarins based on pyridazine scaffold as selective MAO-B inhibitors (2020) Costas-Lago M.C.; Besada P.; Rodríguez-Enríquez F.; Viña D.; Vilar S.; Uriarte E.; Borges F.; Terán C. (Elsevier Masson SAS, 2017)
3-Arylcoumarins as highly potent and selective monoamine oxidase B inhibitors: Which chemical features matter? (2020) Mellado M.; Mella J.; González C.; Viña D.; Uriarte E.; Matos M.J. (Academic Press Inc., 2020)
Timed release of cerebrolysin using drug-loaded titanate nanospheres reduces brain pathology and improves behavioral functions in Parkinson’s disease (2020) Ozkizilcik A.; Sharma A.; Muresanu D.F.; Lafuente J.V.; Ryan Tian Z.; Patnaik R.; Mössler H.; Sharma H.S. (Humana Press Inc., 2018)