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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 Publisher Pubmed



Abolmaali SS1 ; Tamaddon AM2, 5 ; Mohammadi S2 ; Amoozgar Z3 ; Dinarvand R4
Authors
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Authors Affiliations
  1. 1. Pharmaceutical Nanotechnology Department, Shiraz University of Medical Sciences, Shiraz, 71345, Iran
  2. 2. Center for Nanotechnology in Drug Delivery, Shiraz University of Medical Sciences, Shiraz, 71345, Iran
  3. 3. Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute and Harvard Medical School, Boston, 02115, MA, United States
  4. 4. Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, 14174, Iran
  5. 5. Center for Nanotechnology in Drug Delivery, Department of Pharmaceutical Nanotechnology, Shiraz University of Medical Sciences, Shiraz, 71345, Iran

Source: Materials Science and Engineering C Published:2016


Abstract

Self-assembled nanogels were engineered by forming Zn2 +-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 1H-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. © 2016 Elsevier B.V. All rights reserved.