title: Sequential optimization of methotrexate encapsulation in micellar nano-networks of polyethyleneimine ionomer containing redox-sensitive cross-links.
abstract: A functional polycation nanonetwork was developed for delivery of water soluble chemotherapeutic agents. The complexes of polyethyleneimine grafted methoxy polyethylene glycol (PEI-g-mPEG) and Zn(2+) were utilized as the micellar template for cross-linking with dithiodipropionic acid, followed by an acidic pH dialysis to remove the metal ion from the micellar template. The synthesis method was optimized according to pH, the molar ratio of Zn(2+), and the cross-link ratio. The atomic force microscopy showed soft, discrete, and uniform nano-networks. They were sensitive to the simulated reductive environment as determined by Ellman's assay. They showed few positive ζ potential and an average hydrodynamic diameter of 162±10 nm, which decreased to 49±11 nm upon dehydration. The ionic character of the nano-networks allowed the achievement of a higher-loading capacity of methotrexate (MTX), approximately 57% weight per weight, depending on the cross-link and the drug feed ratios. The nano-networks actively loaded with MTX presented some suitable properties, such as the hydrodynamic size of 117±16 nm, polydispersity index of 0.22, and a prolonged swelling-controlled release profile over 24 hours that boosted following reductive activation of the nanonetwork biodegradation. Unlike the PEI ionomer, the nano-networks provided an acceptable cytotoxicity profile. The drug-loaded nano-networks exhibited more specific cytotoxicity against human hepatocellular carcinoma cells if compared to free MTX at concentrations above 1 μM. The enhanced antitumor activity in vitro might be attributed to endocytic entry of MTX-loaded nano-networks that was found in the epifluorescence microscopy experiment for the fluorophore-labeled nano-networks.
authors.affiliation: Department of Pharmaceutics, Shiraz School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran.
authors.forename: Samira Sadat
authors.initials: SS
authors.lastname: Abolmaali
authors.affiliation: Department of Pharmaceutics, Shiraz School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran ; Center for Nanotechnology in Drug Delivery, Shiraz University of Medical Sciences, Shiraz, Iran.
authors.forename: Ali
authors.initials: A
authors.lastname: Tamaddon
authors.affiliation: Department of Pharmaceutics, Shiraz School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran ; Center for Nanotechnology in Drug Delivery, Shiraz University of Medical Sciences, Shiraz, Iran.
authors.forename: Gholamhossein
authors.initials: G
authors.lastname: Yousefi
authors.affiliation: Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
authors.forename: Katayoun
authors.initials: K
authors.lastname: Javidnia
authors.affiliation: Nanotechnology Research Centre, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Rasoul
authors.initials: R
authors.lastname: Dinarvand
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000737:chemistry; D002470:Cell Survival / Q000187:drug effects*; D003432:Cross-Linking Reagents / Q000737:chemistry; D004058:Diffusion; D004655:Emulsions / Q000737:chemistry*; D056945:Hep G2 Cells; D006801:Humans; D008422:Materials Testing; D008727:Methotrexate / Q000008:administration & dosage* / Q000737:chemistry*; D008823:Micelles; D053769:Nanocapsules / Q000008:administration & dosage / Q000737:chemistry* / Q000648:ultrastructure*; D010084:Oxidation-Reduction; D010316:Particle Size; D011094:Polyethyleneimine / Q000737:chemistry*
chemical_list: D000964:Antimetabolites, Antineoplastic; D003432:Cross-Linking Reagents; D004655:Emulsions; D008823:Micelles; D053769:Nanocapsules; D011094:Polyethyleneimine; D008727:Methotrexate
keywords: cytotoxicity; ionomer complex; methotrexate; nanonetwork; polyethyleneimine; template assisted synthesis