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 AM^{2, 5} ; Mohammadi S² ; Amoozgar Z³ ; Dinarvand R⁴ Show Affiliations
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.