Polyvinyl Alcohol (PVA)-Based Nanoniosome for Enhanced in vitro Delivery and Anticancer Activity of Thymol

Abstract

Mohammadreza Abdihaji,1,* Masoumeh Mirzaei Chegeni,2,* Alireza Hadizadeh,3 Negar Farrokhzad,4 Zahra Kheradmand,5 Parastoo Fakhrfatemi,6 Fardad Faress,7 Kasra Moeinabadi-Bidgoli,8 Hassan Noorbazargan,9 Ebrahim Mostafavi10,11 1Department of Biology, The Center for Genomics and Bioinformatics, Indiana University, Bloomington, IN, USA; 2Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran; 3Research Center for Advanced Technologies in Cardiovascular Medicine, Cardiovascular Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran; 4Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK; 5Department of Agriculture, Islamic Azad University Maragheh Branch, Maragheh, Iran; 6Faculty of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran; 7Department of Business, Data Analysis, The University of Texas Rio Grande Valley (UTRGV), Edinburg, TX, USA; 8Basic and Molecular Epidemiology of Gastroenterology Disorders Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran; 9Department of Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; 10Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA; 11Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA*These authors contributed equally to this workCorrespondence: Ebrahim Mostafavi, Email [email protected]; [email protected]: There is an unmet need to develop potent therapeutics against cancer with minimal side effects and systemic toxicity. Thymol (TH) is an herbal medicine with anti-cancer properties that has been investigated scientifically. This study shows that TH induces apoptosis in cancerous cell lines such as MCF-7, AGS, and HepG2. Furthermore, this study reveals that TH can be encapsulated in a Polyvinyl alcohol (PVA)-coated niosome (Nio-TH/PVA) to enhance its stability and enable its controlled release as a model drug in the cancerous region.Materials and Methods: TH-loaded niosome (Nio-TH) was fabricated and optimized using Box–Behnken method and the size, polydispersity index (PDI) and entrapment efficiency (EE) were characterized by employing DLS, TEM and SEM, respectively. Additionally, in vitro drug release and kinetic studies were performed. Cytotoxicity, antiproliferative activity, and the mechanism were assessed by MTT assay, quantitative real-time PCR, flow cytometry, cell cycle, caspase activity evaluation, reactive oxygen species investigation, and cell migration assays.Results: This study demonstrated the exceptional stability of Nio-TH/PVA at 4 °C for two months and its pH-dependent release profile. It also showed its high toxicity on cancerous cell lines and high compatibility with HFF cells. It revealed the modulation of Caspase-3/Caspase-9, MMP-2/MMP-9 and Cyclin D/ Cyclin E genes by Nio-TH/PVA on the studied cell lines. It confirmed the induction of apoptosis by Nio-TH/PVA in flow cytometry, caspase activity, ROS level, and DAPI staining assays. It also verified the inhibition of metastasis by Nio-TH/PVA in migration assays.Conclusion: Overall, the results of this study revealed that Nio-TH/PVA may effectively transport hydrophobic drugs to cancer cells with a controlled-release profile to induce apoptosis while exhibiting no detectable side effects due to their biocompatibility with normal cells.Graphical Abstract: Keywords: herbal anticancer drug, thymol, cancerous cell lines, pH-dependent release, niosome, polyvinyl alcohol, apoptosis

Keywords

• herbal anticancer drug
• thymol
• cancerous cell lines
• ph-dependent release
• niosome
• polyvinyl alcohol
• apoptosis