title: Tailoring Lipid and Polymeric Nanoparticles as siRNA Carriers towards the Blood-Brain Barrier - from Targeting to Safe Administration.
abstract: Blood-brain barrier is a tightly packed layer of endothelial cells surrounding the brain that acts as the main obstacle for drugs enter the central nervous system (CNS), due to its unique features, as tight junctions and drug efflux systems. Therefore, since the incidence of CNS disorders is increasing worldwide, medical therapeutics need to be improved. Consequently, aiming to surpass blood-brain barrier and overcome CNS disabilities, silencing P-glycoprotein as a drug efflux transporter at brain endothelial cells through siRNA is considered a promising approach. For siRNA enzymatic protection and efficient delivery to its target, two different nanoparticles platforms, solid lipid (SLN) and poly-lactic-co-glycolic (PLGA) nanoparticles were used in this study. Polymeric PLGA nanoparticles were around 115 nm in size and had 50 % of siRNA association efficiency, while SLN presented 150 nm and association efficiency close to 52 %. Their surface was functionalized with a peptide-binding transferrin receptor, in a site-oriented manner confirmed by NMR, and their targeting ability against human brain endothelial cells was successfully demonstrated by fluorescence microscopy and flow cytometry. The interaction of modified nanoparticles with brain endothelial cells increased 3-fold compared to non-modified lipid nanoparticles, and 4-fold compared to non-modified PLGA nanoparticles, respectively. These nanosystems, which were also demonstrated to be safe for human brain endothelial cells, without significant cytotoxicity, bring a new hopeful breath to the future of brain diseases therapies.
authors.affiliation: i3S, Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen, 208, 4200-135, Porto, Portugal.|INEB, Instituto de Engenharia Biomédica, Biocarrier Group, Universidade do Porto, Rua Alfredo Allen, 208, 4200-135, Porto, Portugal.|ICBAS, Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313, Porto, Portugal.
authors.forename: Maria João
authors.initials: MJ
authors.lastname: Gomes
authors.affiliation: CIQUP/Departamento de Química, Faculdade de Ciências, Universidade do Porto, Rua do Campo Alegre, 687, 4169-007, Porto, Portugal.
authors.forename: Carlos
authors.initials: C
authors.lastname: Fernandes
authors.affiliation: Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, Campusvej 55, -5230, Odense, DK, Denmark.
authors.forename: Susana
authors.initials: S
authors.lastname: Martins
authors.affiliation: CIQUP/Departamento de Química, Faculdade de Ciências, Universidade do Porto, Rua do Campo Alegre, 687, 4169-007, Porto, Portugal.
authors.forename: Fernanda
authors.initials: F
authors.lastname: Borges
authors.affiliation: i3S, Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen, 208, 4200-135, Porto, Portugal. bruno.sarmento@ineb.up.pt.|INEB, Instituto de Engenharia Biomédica, Biocarrier Group, Universidade do Porto, Rua Alfredo Allen, 208, 4200-135, Porto, Portugal. bruno.sarmento@ineb.up.pt.|Instituto de Investigação e Formação Avançada em Ciências e Tecnologias da Saúde, CESPU, Rua Central de Gandra, 1317, 4585-116, Gandra, Portugal. bruno.sarmento@ineb.up.pt.
authors.forename: Bruno
authors.initials: B
authors.lastname: Sarmento
mesh_terms: D001812:Blood-Brain Barrier / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D001921:Brain / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002461:Cell Line, Transformed; D016503:Drug Delivery Systems / Q000379:methods*; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006579:Heterozygote; D006801:Humans; D019344:Lactic Acid / Q000008:administration & dosage* / Q000378:metabolism; D008055:Lipids / Q000008:administration & dosage*; D053758:Nanoparticles / Q000008:administration & dosage* / Q000378:metabolism; D011100:Polyglycolic Acid / Q000008:administration & dosage* / Q000378:metabolism; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011108:Polymers / Q000008:administration & dosage / Q000378:metabolism; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000235:genetics / Q000378:metabolism
chemical_list: D008055:Lipids; D011108:Polymers; D034741:RNA, Small Interfering; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid
keywords: Blood-brain barrier; Functionalization; Nanoparticles; Targeting; TfR-peptide; siRNA