Preparation of pH-Responsive Vesicular Deferasirox: Evidence from In Silico, In Vitro, and In Vivo Evaluations
Authors: Saman Sargazi
Farshid Zargari
Mohammad Reza Hajinezhad
M Ali Aboudzadeh
Mahmood Barani
Fakhara Sabir
Md Khalid Anwer
Abbas Pardakhty
Abbas Rahdar
Journal: ACS Omega (2021)
Discipline: CHEMISTRY
Keywords: pH-sensitive nanocarriers; anticancer drugs; chemotherapy; pH-responsive deferasirox; vesicle
Affiliations: Medical Mycology and Bacteriology Research Center, Kerman University of Medical Sciences, Kerman 7616913555, Iran, Cellular and Molecular Research Center, Resistant Tuberculosis Institute, Zahedan University of Medical Sciences, Zahedan 9816743463, Iran, Basic Veterinary Science Department, Veterinary Faculty, University of Zabol, Zabol 9861335856, Iran, Department of Physics, University of Zabol, Zabol 9861335856, Iran, Faculty of Pharmacy, Institute of Pharmaceutical Technology and Regulatory Affairs, University of Szeged, Eötvös u. 6, Szeged H-6720, Hungary, Pharmaceutics Research Center, Nauropharmacology Research Institute, Kerman University of Medical Sciences, Kerman 7616913555, Iran, Pharmacology Research Center, Zahedan University of Medical Sciences, Zahedan 9816743463, Iran, Department of Pharmaceutics, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Alkharj 11942, Saudi Arabia, CNRS, University Pau & Pays Adour, E2S UPPA, Institut des Sciences Analytiques et de Physico-Chimie pour l’Environnement et les Matériaux, IPREM, UMR5254, 64000 Pau, France

Abstract:  pH-sensitive nanocarriers can effectively deliver anticancer drugs to tumors and reduce the adverse effects of conventional chemotherapy. In this light, we prepared a novel pH-responsive deferasirox (DFX)-loaded vesicle and comprehensively performed in silico, in vitro, and in vivo studies to examine the properties of the newly synthesized formulation. Physiochemical assessment of the developed formulations showed that they have an average size (107 ± 2 nm), negative zeta potential (-29.1 ± 1.5 mV), high encapsulation efficiency (84.2 ± 2.6%), and a pH-responsive release. Using the molecular dynamics simulation, the structural and dynamic properties of ergosterol-containing niosomes (ST60/Ergo) in the presence of DFX molecules were analyzed and showed a good interaction between DFX and vesicle components. Cytotoxic assessment showed that niosomal DFX exhibited a greater cytotoxic effect than free DFX in both human cancer cells (MCF-breast cancer and Hela cervical cancer) and induced evident morphological features of apoptotic cell death. No marked difference between the ability of free and niosomal DFX was found in activating caspase-3 in Hela cells. Eight weeks of intraperitoneal administrations of free DFX at three doses caused a significant increase in serum biochemical parameters and liver lipid peroxidation. Treatment with 5 mg/kg dose of niosomal DFX caused a significant increase in serum creatinine (P &lt; 0.05); however, other parameters remained unchanged. On the other hand, administration of niosomal DFX at the highest dose (10 mg/kg) significantly increased serum creatinine (P &lt; 0.05), BUN, and serum liver enzymes compared to the control rats (P &lt; 0.001). Based on the results, the application of pH-responsive DFX-loaded niosomes, as a novel drug delivery platform, may yield promising results in cancer treatment. 

Retracted: No

PubPeer comments:
 This paper shares an issue with another by the same group already commented on PubPeer. It arises here in the results shown in Figure 3, where the authors claim to have observed both proplatelet formation and platelet production by cultured megakaryocytes u2013 in this case derived from mice. It is well established in the literature that platelet production by megakaryocytes requires conditions that recreate key aspects of bone marrow physiology that include blood flow, turbulence and exposure to vascular endothelium. Thus platelet production does not occur in static culture to any meaningful extent, and efforts are underway to establish systems where platelet production is sufficient ex vivo to generate transfusable cells. Nevertheless, the authors claim they generated sufficient platelets from cultured megakaryocytes to assess the effects of treatment with anti-CD41 antibody with or without additional LLLT u2013 the effect of the latter being minimal relative to untreated controls. Can the authors provide evidence regarding the numbers and morphology of the platelets they claim to have generated in these experiments? , 
 In Figure 3, the authors claim to have observed both proplatelet formation and platelet production by cultured mouse megakaryocytes. It is well established in the literature that platelet production by megakaryocytes requires conditions that recreate key aspects of bone marrow physiology that include blood flow, turbulence and exposure to vascular endothelium. Thus while structures resembling proplatelets can sometimes be observed in in a small percentage of megakaryocytes cultured from marrow u2013 as done in this study - platelet production does not occur in static culture to any meaningful extent. The authors claim they generated sufficient platelets from cultured megakaryocytes to assess the effects of treatment with anti-CD41 antibody with or without additional LLLT, with the effect of the latter being minimal relative to untreated controls. Can the authors provide evidence regarding the numbers and morphology of the platelets they generated in these experiments? ,