Surface Functionalization of PLGAA Nanoparticles to Increase Transport across the BBB for Alzheimer's Disease  
[PERSON]  
1 Department of Pharmacy, Pharmaceutical Technology and Physical Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, 08028 Barcelona, Spain; [EMAIL_ADDRESS] (L.D.A.);  
[PERSON]  
1 Department of Pharmacy, Pharmaceutical Technology and Physical Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, 08028 Barcelona, Spain; [EMAIL_ADDRESS] (L.D.A.);  
2 Institute of Nanoscience and Nanotechnology (IN2 UB), University of Barcelona, 08028 Barcelona, Spain 2  
[PERSON]  
3 Centro de Investigacion Biomedica en Red de Enfermedades Neurodepeneratives (CIBERNED), University of Barcelona, 08028 Barcelona, Spain; mirentchetto@ubde (M.E.);  
4 Research Center and Memory Clinic, Fundacio ACE. Institut Catal de Neurochencies (Arplaces-International University of Catalunya (UIC), 08017 Barcelona, Spain 4  
[PERSON]  
6 CEB-Centre of Biological Engineering, University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal;  
6 [EMAIL_ADDRESS] (M.E.);  
7 Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Coimbra, 3000-458 Coimbra, Portugal 7  
[PERSON]  
1 Department of Pharmacy, Pharmaceutical Technology and Physical Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, 08028 Barcelona, Spain; [EMAIL_ADDRESS] (L.D.A.);  
2 Institute of Nanoscience and Nanotechnology (IN2 UB), University of Barcelona, 08028 Barcelona, Spain 2  
[PERSON]  
3 Centro de Investigacion Biomedica en Red de Enfermedades Neurodepeneratives (CIBERNED), University of Barcelona, 08028 Barcelona, Spain; mirentchetto@ubde (M.E.);  
4 Research Center and Memory Clinic, Fundacio ACE. Institut Catal de Neurochencies (Arplaces-International University of Catalunya (UIC), 08017 Barcelona, Spain 4  
[PERSON]  
1 Department of Pharmacy, Pharmaceutical Technology and Physical Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, 08028 Barcelona, Spain 123344  
Therefore, several innovative strategies have been proposed to enhance the transport of therapeutics through the BBB [3]. Among different types of nanosized particles, polymeric (e.g., PLGA-NPs, PLA-NPs, polymeric micelles, dendrimers) and lipid (e.g., liposomes, solid lipid nanoparticles) nanoparticles have been extensively studied to deliver therapeutic drugs and macromolecules to the brain [4].  
In this area, polymeric nanoparticles can be made of biocompatible copolymers of poly(D,L-lactic-co-glycolic) acid that have low solubility in water [5,6]. Moreover, characteristics such as size, zeta potential and hydrophilicity can be controlled by surface modifications, such as surfactant coating, to enhance brain uptake [7]. In addition, ligands known to target the surface receptors on endothelial cells of the BBB (e.g., transferrin, insulin and lipoprotein receptors) can be linked to the surface of PLGA-NPs to provide targeted brain delivery and improve NP uptake [8].  
PLGA is, indeed, one of the most successful polymeric materials used to produce functionalized particles, given its biodegradability and biocompatibility properties that have contributed to its approval by the FDA and EMA (1986) for parenteral administration. Besides, the loading of drugs into a polymeric matrix core of nanoparticles promotes drug protection against degradation and offers the possibility to modify the release profile both in vitro and in vivo [9].  
The aim of the present work is to identify different strategies of PLGA-NPs surface functionalization to enhance their transport through the BBB for successful treatment of neurodegenerative diseases, in particular for AD. In order to undertake this objective, some secondary aims have been established, such as the thorough analysis of AD pathology highlighting the challenges encountered in the physiological properties of the BBB for drug delivery, the role of PLGA NPs and their surface targeting to increase transport through the BBB for AD treatment.