Mn(II) & Gd(III) deferrioxamine complex contrast agents & temozolomide cancer prodrug immobilized on folic acid targeted graphene/polyacrylic acid nanocarrier: MRI efficiency, drug stability & interactions with cancer cells

Abstract

Nanocomposite systems, consisting of the reduced graphene oxide/polyacrylic acid as nanocarrier, integrated with folic acid targeting agent and further modified by Deferrioxamine-M (M: Mn2+ or Gd3+) as the diagnostic MRI contrast agents or Temozolomide as a therapeutic agent, abbreviated as (i) GNs@PAA-DFO-Mn(II)/FOA, (ii) GNs@PAA-DFO-Gd(III)/FOA, and (iii) GNs@PAA-FOA/TMZ, were synthesized, characterized, and examined for B16F10 Melanoma cells through in-vitro/in-vivo methods. Physicochemical characterization of the prepared systems was performed by using DLS, zeta-potential, TEM, FTIR, UV-vis, XPS, fluorescence, and electrochemical methods. The biocompatibility of the nanocarrier was implicated according to the histopathological evaluation of the H&E stained sections of vital organs. Release studies at biological pH 7.4, revealed good stability for TMZ immobilized on the GNs@PAA-FOA/TMZ nanocarrier. The in-vitro MRI studies of the GNs@PAA-DFO-Mn(II)/FOA and GNs@PAA-DFO-Gd(III)/FOA systems revealed longitudinal relaxivities of 13.00 and 20.64 mM(-1) s(-1), using variations of the spin-lattice relaxation rates (r(1) = 1/T1) as a function of the systems concentrations, respectively. These systems were studied further by the in-vivo method. The obtained images supported their ability for MRI imaging. The intracellular delivery of the system was monitored and supported by flow cytometry based on PI florescent dye loaded onto the introduced nanocarrier, GNs@PAA-FOA/PI. The interaction of the GCE-GNs@PAA-FOA/TMZ, GCE-GNs@PAA-DFO-Mn(II)/FOA, and GCE-GNs@PAA-DFO-Gd(III)]/FOA systems with cancer cells was investigated through electrochemical impedance spectroscopy. The results showed a high affinity of the systems toward B16F10 Melanoma cells with the selectivity degrees of 12.96, 9.92, and 9.62, respectively, compared with L929 cells.