gels Review New Horizons in Hydrogels for Methotrexate Delivery Ali Dehshahri 1 , Anuj Kumar 2 , Vijay Sagar Madamsetty 3 , Ilona Uzieliene 4 , Shima Tavakol 5 , Fereshteh Azedi 5,6 , Hojjat Samareh Fekri 7,8 , Ali Zarrabi 9 , Reza Mohammadinejad 10, * and Vijay Kumar Thakur 11, *   Citation: Dehshahri, A.; Kumar, A.; Madamsetty, V.S.; Uzieliene, I.; Tavakol, S.; Azedi, F.; Fekri, H.S.; Zarrabi, A.; Mohammadinejad, R.; Thakur, V.K.et al. New Horizons in Hydrogels for Methotrexate Delivery. Gels 2021, 7, 2. https://doi.org/ 10.3390/gels7010002 Received: 10 November 2020 Accepted: 21 December 2020 Published: 30 December 2020 Publisher’s Note: MDPI stays neu- tral with regard to jurisdictional clai- ms in published maps and institutio- nal affiliations. Copyright: © 2020 by the authors. Li- censee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and con- ditions of the Creative Commons At- tribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). 1 Center for Nanotechnology in Drug Delivery, Shiraz University of Medical Sciences, Shiraz 7146864685, Iran; dehshahria@sums.ac.ir 2 School of Chemical Engineering, Yeungnam University, 280 Daehak-Ro, Gyeongsan 38541, Korea; anuj.budhera@gmail.com 3 Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine and Science, Jacksonville, FL 32224, USA; sagarchemistry@gmail.com 4 Department of Regenerative Medicine, State Research Institute Centre for Innovative Medicine, Santariskiu 5, LT-08406 Vilnius, Lithuania; ilona.uzieliene@imcentras.lt 5 Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran 1449614525, Iran; shima.tavakol@yahoo.com (S.T.); azeditehrani.f@iums.ac.ir (F.A.) 6 Department of Neuroscience, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran 1449614535, Iran 7 Student Research Committee, Kerman University of Medical Sciences, Kerman 7619813159, Iran; hojjatfekri@gmail.com 8 Pharmaceutics Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman 7616911319, Iran 9 Sabanci University Nanotechnology Research and Application Center (SUNUM), Tuzla, Istanbul 34956, Turkey; alizarrabi@sabanciuniv.edu 10 Research Center for Tropical and Infectious Diseases, Kerman University of Medical Sciences, Kerman 7618866749, Iran 11 Biorefining and Advanced Materials Research Center, Scotland’s Rural College (SRUC), Kings Buildings, West Mains Road, Edinburgh EH9 3JG, UK * Correspondence: r.mohammadinejad@kmu.ac.ir (R.M.); Vijay.Thakur@sruc.ac.uk (V.K.T.) Abstract: Since its first clinical application, methotrexate (MTX) has been widely used for the treatment of human diseases. Despite great advantages, some properties such as poor absorption, short plasma half-life and unpredictable bioavailability have led researchers to seek novel delivery systems to improve its characteristics for parenteral and oral administration. Recently, great attention has been directed to hydrogels for the preparation of MTX formulations. This review describes the potential of hydrogels for the formulation of MTX to treat cancer, rheumatoid arthritis, psoriasis and central nervous system diseases. We will delineate the state-of-the-art and promising potential of hydrogels for systemic MTX delivery as well as transdermal delivery of the drug-using hydrogel- based formulations. Keywords: methotrexate; drug delivery; hydrogels; cancer; rheumatoid arthritis; psoriasis 1. Introduction Methotrexate (MTX) has been considered as a standard therapeutic agent for various diseases including cancer and autoimmune diseases [1]. Regarding the potential effect of folic acid antagonists in the treatment of childhood leukemia, two molecules were synthesized as folic acid competitive inhibitors called aminopterin and amethopterin (methotrexate, MTX). It was found that MTX is less toxic and more stable than its analogue aminopterin. Therefore, it was first used for the treatment of acute leukemia in children [2]. Since the 1940s, the clinical applications of MTX has not been limited to treat various neoplasms such as acute myeloid leukemia, osteosarcomas, non-Hodgkin’s lymphoma, breast and bladder cancers [3–5]. The potential of MTX for rheumatoid arthritis was also Gels 2021, 7, 2. https://doi.org/10.3390/gels7010002 https://www.mdpi.com/journal/gels