title: Chemically crosslinked nanogels of PEGylated poly ethyleneimine (l-histidine substituted) synthesized via metal ion coordinated self-assembly for delivery of methotrexate: Cytocompatibility, cellular delivery and antitumor activity in resistant cells.
abstract: Self-assembled nanogels were engineered by forming Zn(2+)-coordinated micellar templates of PEGylated poly ethyleneimine (PEG-g-PEI), chemical crosslinking and subsequent removal of the metal ion. Creation of stable micellar templates is a crucial step for preparing the nanogels. To this aim, imidazole moieties were introduced to the polymer by Fmoc-l-histidine using carbodiimide chemistry. It was hypothesized the nanogels loaded with methotrexate (MTX), a chemotherapeutic agent, circumvent impaired carrier activity in HepG2 cells (MTX-resistant hepatocellular carcinoma). So, the nanogels were post-loaded with MTX and characterized by (1)H-NMR, FTIR, dynamic light scattering-zeta potential, atomic force microscopy, and drug release experiments. Cellular uptake and the antitumor activity of MTX-loaded nanogels were investigated by flow cytometry and MTT assay. Discrete, spherical and uniform nanogels, with sizes about 77-83 nm and a relatively high drug loading (54 ± 4% w/w), showed a low polydispersity and neutral surface charges. The MTX-loaded nanogels, unlike empty nanogels, lowered viability of HepG2 cells; the nanogels demonstrated cell-cycle arrest and apoptosis comparably higher than MTX as free drug that was shown to be through i) cellular uptake of the nanogels by clathrin-mediated transport and ii) endosomolytic activity of the nanogels in HepG2 cells. These findings indicate the potential antitumor application of this preparation, which has to be investigated in-vivo.
authors.affiliation: Pharmaceutical Nanotechnology Department, Shiraz University of Medical Sciences, Shiraz 71345, Iran. Electronic address: s.abolmaali@gmail.com.
authors.forename: Samira Sadat
authors.initials: SS
authors.lastname: Abolmaali
authors.affiliation: Center for Nanotechnology in Drug Delivery, Shiraz University of Medical Sciences, Shiraz 71345, Iran. Electronic address: amtamadon@gmail.com.
authors.forename: Ali Mohammad
authors.initials: AM
authors.lastname: Tamaddon
authors.affiliation: Center for Nanotechnology in Drug Delivery, Shiraz University of Medical Sciences, Shiraz 71345, Iran. Electronic address: samaneh.mohammadi1986@gmail.com.
authors.forename: Samaneh
authors.initials: S
authors.lastname: Mohammadi
authors.affiliation: Department of Cancer Immunology and Aids, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA. Electronic address: zohreh_amoozgar@dfci.harvard.edu.
authors.forename: Zohreh
authors.initials: Z
authors.lastname: Amoozgar
authors.affiliation: Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran 14174, Iran. Electronic address: dinarvand@tums.ac.ir.
authors.forename: Rasoul
authors.initials: R
authors.lastname: Dinarvand
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D004337:Drug Carriers / Q000737:chemistry*; D065546:Drug Liberation; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D000067493:Dynamic Light Scattering; D056945:Hep G2 Cells; D006639:Histidine / Q000737:chemistry; D006801:Humans; D007477:Ions / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D008670:Metals / Q000737:chemistry*; D008727:Methotrexate / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity; D018625:Microscopy, Atomic Force; D000080385:Nanogels; D010316:Particle Size; D011092:Polyethylene Glycols / Q000737:chemistry*; D011094:Polyethyleneimine / Q000737:chemistry*; D017550:Spectroscopy, Fourier Transform Infrared
chemical_list: D000964:Antimetabolites, Antineoplastic; D004337:Drug Carriers; D007477:Ions; D008670:Metals; D000080385:Nanogels; C413692:polyethylene glycol polyethyleneimine nanogel; C033223:polyhistidine; D011092:Polyethylene Glycols; D006639:Histidine; D011094:Polyethyleneimine; D008727:Methotrexate
keywords: Antitumor activity; Cellular delivery; Cytocompatibility; In-vitro; Methotrexate; PEGylated poly ethyleneimine; Self-assembled nanogel; l-Histidine substitution