Hafiz S Sarwar1, Sehreen Ashraf2, Sohail Akhtar3, Muhammad F Sohail1,4,5, Syed Z Hussain6, Muhammad Rafay7, Masoom Yasinzai8, Irshad Hussain6,9, Gul Shahnaz1,10. 1. Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, 45320, Pakistan. 2. Department of Biotechnology, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, 45320, Pakistan. 3. Department of Entomology, University College of Agriculture & Environmental Sciences, The Islamia University, Bahawalpur, Pakistan. 4. Department of Medicine, Biomaterials Innovation Research Center, Brigham & Women's Hospital, Harvard Medical School, Cambridge, MA 02139, USA. 5. Riphah Institute of Pharmaceutical Sciences, Riphah International University, Lahore Campus, Lahore, Pakistan. 6. Department of Chemistry, SBA School of Science & Engineering (SBASSE), Lahore University of Management Sciences (LUMS), Lahore, 54792, Pakistan. 7. Department of Forestry, Range & Wild Life Management, University College of Agriculture, Islamia University, Bahawalpur, Pakistan. 8. Center for Interdisciplinary Research in Biological Sciences, International Islamic University, Islamabad, Pakistan. 9. US-Pakistan Center for Advanced Studies in Energy (USPCAS-E), University of Engineering & Technology (UET), Peshawar, Pakistan. 10. Department of Pathology, College of Medicine, The Ohio State University, Columbus, OH 43210, USA.
Abstract
AIM: Our aim was to inhibit trypanothione reductase (TR) and P-gp efflux pump of Leishmania by the use of thiolated polymers. Thus, increasing the intracellular accumulation and therapeutic effectiveness of antimonial compounds. METHODS: Mannosylated thiolated chitosan and mannosylated thiolated chitosan-polyethyleneimine graft were synthesized and characterized. Meglumine antimoniate-loaded nanoparticles were prepared and evaluated for TR and P-gp efflux pump inhibition, biocompatibility, macrophage uptake and antileishmanial potential. RESULTS: Thiomers inhibited TR with Ki 2.021. The macrophage uptake was 33.7- and 18.9-fold higher with mannosylated thiolated chitosan-polyethyleneimine graft and mannosylated thiolated chitosan nanoparticles, respectively, as compared with the glucantime. Moreover, the in vitro antileishmanial activity showed 14.41- and 7.4-fold improved IC50 for M-TCS-g-PEI and M-TCS, respectively as compared with glucantime. CONCLUSION: These results encouraged the concept that TR and P-gp inhibition by the use of thiomers improves the therapeutic efficacy of antimonial drugs.
AIM: Our aim was to inhibit trypanothione reductase (TR) and P-gp efflux pump of Leishmania by the use of thiolated polymers. Thus, increasing the intracellular accumulation and therapeutic effectiveness of antimonial compounds. METHODS: Mannosylated thiolated chitosan and mannosylated thiolated chitosan-polyethyleneimine graft were synthesized and characterized. Meglumine antimoniate-loaded nanoparticles were prepared and evaluated for TR and P-gp efflux pump inhibition, biocompatibility, macrophage uptake and antileishmanial potential. RESULTS:Thiomers inhibited TR with Ki 2.021. The macrophage uptake was 33.7- and 18.9-fold higher with mannosylated thiolated chitosan-polyethyleneimine graft and mannosylated thiolated chitosan nanoparticles, respectively, as compared with the glucantime. Moreover, the in vitro antileishmanial activity showed 14.41- and 7.4-fold improved IC50 for M-TCS-g-PEI and M-TCS, respectively as compared with glucantime. CONCLUSION: These results encouraged the concept that TR and P-gp inhibition by the use of thiomers improves the therapeutic efficacy of antimonial drugs.
Authors: Juliane S Lanza; Virginia M R Vallejos; Guilherme S Ramos; Ana Carolina B de Oliveira; Cynthia Demicheli; Luis Rivas; Sébastien Pomel; Philippe M Loiseau; Frédéric Frézard Journal: Pharmaceutics Date: 2022-08-21 Impact factor: 6.525