title: Novel functionalization strategies of polymeric nanoparticles as carriers for brain medications.
abstract: For targeted brain delivery, nanoparticles (NPs) should bypass the blood-brain barrier (BBB). Novel functionalization strategies, based on low-density lipoprotein receptor (LDLR) binding domain, have been here tested to increase the brain targeting efficacy of poly d,l-lactic-co-glycolic acid (PLGA) NPs, biodegradable and suited for biomedical applications. Custom-made PLGA NPs were functionalized with an apolipoprotein E modified peptide (pep-apoE) responsible for LDLR binding, or with lipocalin-type prostaglandin-d-synthase (L-PGDS), highly expressed in the brain. At the comparison of pep-apoE and L-PGDS sequences, a highly homologs region was here identified, indicating that also L-PGDS could bind LDLR. Non-functionalized and functionalized NPs did not affect the viability of cultured human dendritic cells, protagonists of the immune response, and did not activate them to a proinflammatory profile. At 2 h after intravenous injection in mice, functionalized, but not the non-functionalized ones, fluorescent-tagged NPs were observed in the cerebral cortex parenchyma. The NPs were mostly internalized by neurons and microglia; glial cells showed a weak activation. The findings indicate that the tested functionalization strategies do not elicit adverse immune responses and that the peptidic moieties enable BBB traversal of the NPs, thus providing potential brain drug carriers. These could be especially effective for brain diseases in which LDLR is involved. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 847-858, 2017.
authors.affiliation: Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Verona, Italy.
authors.forename: Corinne
authors.initials: C
authors.lastname: Portioli
authors.affiliation: Department of Biotechnology, University of Verona, Verona, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Bovi
authors.affiliation: Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Verona, Italy.
authors.forename: Donatella
authors.initials: D
authors.lastname: Benati
authors.affiliation: Department of Medicine, University of Verona, Verona, Italy.
authors.forename: Marta
authors.initials: M
authors.lastname: Donini
authors.affiliation: Department of Biotechnology, University of Verona, Verona, Italy.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Perduca
authors.affiliation: Department of Computer Science, University of Verona, Verona, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Romeo
authors.affiliation: Department of Medicine, University of Verona, Verona, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Dusi
authors.affiliation: Department of Biotechnology, University of Verona, Verona, Italy.
authors.forename: Hugo L
authors.initials: HL
authors.lastname: Monaco
authors.affiliation: Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Verona, Italy.
authors.forename: Marina
authors.initials: M
authors.lastname: Bentivoglio
mesh_terms: D001057:Apolipoproteins E / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D001812:Blood-Brain Barrier / Q000378:metabolism*; D002540:Cerebral Cortex / Q000378:metabolism*; D016503:Drug Delivery Systems / Q000379:methods*; D005260:Female; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D019344:Lactic Acid / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D054834:Lipocalins / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D008297:Male; D053758:Nanoparticles / Q000737:chemistry / Q000627:therapeutic use; D010455:Peptides / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D011100:Polyglycolic Acid / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011973:Receptors, LDL / Q000737:chemistry*
chemical_list: D001057:Apolipoproteins E; C573412:LDLR protein, human; D054834:Lipocalins; D010455:Peptides; D011973:Receptors, LDL; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D019746:Intramolecular Oxidoreductases; C022466:prostaglandin R2 D-isomerase
keywords: apolipoprotein E; brain delivery; functionalized PLGA nanoparticles; immune response; lipocalin type prostaglandin D synthase