title: Nanoparticles of alkylglyceryl-dextran-graft-poly(lactic acid) for drug delivery to the brain: Preparation and in vitro investigation.
abstract: Poly(lactic acid), which has an inherent tendency to form colloidal systems of low polydispersity, and alkylglyceryl-modified dextran - a material designed to combine the non-immunogenic and stabilising properties of dextran with the demonstrated permeation enhancing ability of alkylglycerols - have been combined for the development of nanoparticulate, blood-brain barrier-permeating, non-viral vectors. To this end, dextran, that had been functionalised via treatment with epoxide precursors of alkylglycerol, was covalently linked to poly(lactic acid) using a carbodiimide cross-linker to form alkylglyceryl-modified dextran-graft-poly(lactic acid). Solvent displacement and electrospray methods allowed the formulation of these materials into nanoparticles having a unimodal size distribution profile of about 100-200nm and good stability at physiologically relevant pH (7.4). The nanoparticles were characterised in terms of hydrodynamic size (by Dynamic Light Scattering and Nanoparticle Tracking Analysis), morphology (by Scanning Electron Microscopy and Atomic Force Microscopy) and zeta potential, and their toxicity was evaluated using MTT and PrestoBlue assays. Cellular uptake was evidenced by confocal microscopy employing nanoparticles that had been loaded with the easy-to-detect Rhodamine B fluorescent marker. Transwell-model experiments employing mouse (bEnd3) and human (hCMEC/D3) brain endothelial cells revealed enhanced permeation (statistically significant for hCMEC/D3) of the fluorescent markers in the presence of the nanoparticles. Results of studies using Electric Cell Substrate Impedance Sensing suggested a transient decrease of the barrier function in an in vitro blood-brain barrier model following incubation with these nanoformulations. An in ovo study using 3-day chicken embryos indicated the absence of whole-organism acute toxicity effects. The collective in vitro data suggest that these alkylglyceryl-modified dextran-graft-poly(lactic acid) nanoparticles are promising candidates for in vivo evaluations that would test their capability to transport therapeutic actives to the brain.
authors.affiliation: School of Pharmacy and Biomedical Sciences, University of Portsmouth, St Michael's Building, White Swan Road, Portsmouth PO1 2DT, United Kingdom.
authors.forename: Petr
authors.initials: P
authors.lastname: Toman
authors.affiliation: School of Pharmacy and Biomedical Sciences, University of Portsmouth, St Michael's Building, White Swan Road, Portsmouth PO1 2DT, United Kingdom.
authors.forename: Chun-Fu
authors.initials: CF
authors.lastname: Lien
authors.affiliation: Leicester School of Pharmacy, De Montfort University, Leicester LE1 9BH, United Kingdom.
authors.forename: Zeeshan
authors.initials: Z
authors.lastname: Ahmad
authors.affiliation: School of Pharmacy and Biomedical Sciences, University of Portsmouth, St Michael's Building, White Swan Road, Portsmouth PO1 2DT, United Kingdom.
authors.forename: Susanne
authors.initials: S
authors.lastname: Dietrich
authors.affiliation: School of Pharmacy and Biomedical Sciences, University of Portsmouth, St Michael's Building, White Swan Road, Portsmouth PO1 2DT, United Kingdom.
authors.forename: James R
authors.initials: JR
authors.lastname: Smith
authors.affiliation: School of Pharmacy and Biomedical Sciences, University of Portsmouth, St Michael's Building, White Swan Road, Portsmouth PO1 2DT, United Kingdom.
authors.forename: Qian
authors.initials: Q
authors.lastname: An
authors.affiliation: School of Pharmacy and Biomedical Sciences, University of Portsmouth, St Michael's Building, White Swan Road, Portsmouth PO1 2DT, United Kingdom.
authors.forename: Éva
authors.initials: É
authors.lastname: Molnár
authors.affiliation: School of Pharmacy and Biomedical Sciences, University of Portsmouth, St Michael's Building, White Swan Road, Portsmouth PO1 2DT, United Kingdom.
authors.forename: Geoffrey J
authors.initials: GJ
authors.lastname: Pilkington
authors.affiliation: School of Pharmacy and Biomedical Sciences, University of Portsmouth, St Michael's Building, White Swan Road, Portsmouth PO1 2DT, United Kingdom.
authors.forename: Darek C
authors.initials: DC
authors.lastname: Górecki
authors.affiliation: School of Pharmacy and Biomedical Sciences, University of Portsmouth, St Michael's Building, White Swan Road, Portsmouth PO1 2DT, United Kingdom.
authors.forename: John
authors.initials: J
authors.lastname: Tsibouklis
authors.affiliation: School of Pharmacy and Biomedical Sciences, University of Portsmouth, St Michael's Building, White Swan Road, Portsmouth PO1 2DT, United Kingdom. Electronic address: eugen.barbu@port.ac.uk.
authors.forename: Eugen
authors.initials: E
authors.lastname: Barbu
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000737:chemistry*; D002460:Cell Line; D003911:Dextrans / Q000737:chemistry*; D004058:Diffusion; D004339:Drug Compounding / Q000379:methods; D042783:Endothelial Cells / Q000737:chemistry*; D019344:Lactic Acid / Q000737:chemistry*; D051379:Mice; D053769:Nanocapsules / Q000008:administration & dosage / Q000737:chemistry* / Q000648:ultrastructure; D010316:Particle Size; D011091:Polyesters; D011108:Polymers / Q000737:chemistry*
chemical_list: D003911:Dextrans; D053769:Nanocapsules; D011091:Polyesters; D011108:Polymers; D019344:Lactic Acid; C033616:poly(lactide)
keywords: Alkylglycerols; Butylglyceryldextran; Drug delivery; Nanoparticles; Poly(lactic acid)