title: AN in vitro evaluation of a carmustine-loaded Nano-co-Plex for potential magnetic-targeted intranasal delivery to the brain.
abstract: Targeted delivery of carmustine (BCNU), an efficient brain tumor therapeutic, has been challenged with bioavailability issues due to the Blood Brain Barrier (BBB). The currently effective delivery approach is by implants at the site of the tumor, but this is highly invasive. The intranasal route, which is non-invasive and bypasses the BBB, may be alternative route for delivering BCNU to the brain. In this work, polyvinyl alcohol/polyethyleneimine/fIuorecein isothiocyanate complex (Polyplex) coated iron-oxide nanoparticles (Magnetite) were synthesized employing co-precipitation, epoxidation and EDC/NHS coupling reactions. The Polyplex coated magnetite (Nano-co-Plex) was loaded with BCNU for potential magnetically targeted delivery to the brain following intranasal administration. The Nano-co-Plex was characterized employing Thermogravimetric analysis (TGA), Superconducting Quantum Interference Device (SQUID) magnetometry, Fourier Transform Infrared Spectroscopy (FTIR), Nuclear Magnetic Resonance (NMR), X-ray Diffractometry (XRD), Transmission Electron Microscopy (TEM) and Zetasize analysis. Results revealed superparamagnetic hexagonally shaped "core-shell" nanoparticles with cell labeling attributes, of size ranging between 30-50 nm, and a zeta potential value of + 32 ± 2 mV. The Nano-co-Plex synthesized was found to possess high degree of crystallinity with 32% Polyplex coating. The loading and release studies indicated a time-dependent loading with maximum loading capacity of 176.82 μg BCNU/mg of the carrier and maximum release of 75.8% of the loaded BCNU. Cytotoxicity of the BCNU-loaded Nano-co-Plex displayed superiority over the conventional BCNU towards human glioblastoma (HG) cells. Cell studies revealed enhanced uptake and internalization of BCNU-loaded Nano-co-plex in HG cells in the presence of an external magnetic field. These Nano-co-Plexes may be ideal as an intranasal magnetic drug targeting device for BCNU delivery.
authors.affiliation: Wits Advanced Drug Delivery Platform Research Unit, Department of Pharmacy and Pharmacology, School of Therapeutic Sciences, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, 7 York Road, Parktown, 2193, South Africa.
authors.forename: Olufemi D
authors.initials: OD
authors.lastname: Akilo
authors.affiliation: Wits Advanced Drug Delivery Platform Research Unit, Department of Pharmacy and Pharmacology, School of Therapeutic Sciences, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, 7 York Road, Parktown, 2193, South Africa.
authors.forename: Yahya E
authors.initials: YE
authors.lastname: Choonara
authors.affiliation: Highly Correlated Matter Research Group, Department of Physics, University of Johannesburg, Kingsway Road, Auckland Park, 2006, Johannesburg, South Africa.
authors.forename: André M
authors.initials: AM
authors.lastname: Strydom
authors.affiliation: Wits Advanced Drug Delivery Platform Research Unit, Department of Pharmacy and Pharmacology, School of Therapeutic Sciences, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, 7 York Road, Parktown, 2193, South Africa.
authors.forename: Lisa C
authors.initials: LC
authors.lastname: du Toit
authors.affiliation: Wits Advanced Drug Delivery Platform Research Unit, Department of Pharmacy and Pharmacology, School of Therapeutic Sciences, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, 7 York Road, Parktown, 2193, South Africa.
authors.forename: Pradeep
authors.initials: P
authors.lastname: Kumar
authors.affiliation: Division of Neurosciences, Department of Neurology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, 7 York Road, Parktown, 2193, South Africa.
authors.forename: Girish
authors.initials: G
authors.lastname: Modi
authors.affiliation: Wits Advanced Drug Delivery Platform Research Unit, Department of Pharmacy and Pharmacology, School of Therapeutic Sciences, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, 7 York Road, Parktown, 2193, South Africa. Electronic address: viness.pillay@wits.ac.za.
authors.forename: Viness
authors.initials: V
authors.lastname: Pillay
mesh_terms: D000281:Administration, Intranasal; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology; D001921:Brain / Q000378:metabolism; D002330:Carmustine / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D016503:Drug Delivery Systems; D065546:Drug Liberation; D016650:Fluorescein-5-isothiocyanate / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology; D005456:Fluorescent Dyes / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D058185:Magnetite Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D010316:Particle Size; D011094:Polyethyleneimine / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology; D011142:Polyvinyl Alcohol / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology
chemical_list: D018906:Antineoplastic Agents, Alkylating; D005456:Fluorescent Dyes; D058185:Magnetite Nanoparticles; D011142:Polyvinyl Alcohol; D011094:Polyethyleneimine; D016650:Fluorescein-5-isothiocyanate; D002330:Carmustine
keywords: Blood brain barrier; Brain tumor; Carmustine; Chemotherapeutics; Core-shell; Iron oxide nanoparticles; Magnetite; Nano-co-Plex; Polyplex; Superparamagnetic