Investigating the superiority of chitosan/D-alpha-tocopheryl polyethylene glycol succinate binary coated bilosomes in promoting the cellular uptake and anti-SARS-CoV-2 activity of polyphenolic herbal drug candidate

Mohamed Y Zakaria; Marwa Sharaky; Ayman M Noreddin; Radwan Alnajjar; Rabeh El-Shesheny; Omnia Kutkat; Mohamed E El-Beeh; Mohammed A S Abourehab; Ahmed A Al-Karmalawy

doi:10.1016/j.ijpharm.2023.123385

Investigating the superiority of chitosan/D-alpha-tocopheryl polyethylene glycol succinate binary coated bilosomes in promoting the cellular uptake and anti-SARS-CoV-2 activity of polyphenolic herbal drug candidate

Int J Pharm. 2023 Nov 5:646:123385. doi: 10.1016/j.ijpharm.2023.123385. Epub 2023 Sep 9.

Authors

Mohamed Y Zakaria¹, Marwa Sharaky², Ayman M Noreddin³, Radwan Alnajjar⁴, Rabeh El-Shesheny⁵, Omnia Kutkat⁵, Mohamed E El-Beeh⁶, Mohammed A S Abourehab⁷, Ahmed A Al-Karmalawy⁸

Affiliations

¹ Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Port Said University, Port Said 42526, Egypt; Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, King Salman International University, Ras Sudr 46612, South Sinai, Egypt. Electronic address: mohamed.zakaria@pharm.psu.edu.eg.
² Cancer Biology Department, Pharmacology Unit, National Cancer Institute (NCI), Cairo University, Cairo, Egypt.
³ Department of Clinical Pharmacy, Faculty of Pharmacy, Ahram Canadian University, 6th of October City, Giza 12566, Egypt; Department of Internal Medicine, School of Medicine, University of California -Irvine, USA.
⁴ Department of Chemistry, Faculty of Science, University of Benghazi, Benghazi, Libya; PharmD, Faculty of Pharmacy, Libyan International Medical University, Benghazi, Libya; Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa.
⁵ Center of Scientific Excellence for Influenza Viruses, Water Pollution Research Department, Environmental Research Institute, National Research Centre, Dokki-Giza 12622, Egypt.
⁶ Biology Department, Al-Jumum University College, Umm Al-Qura University, Makkah 21955, Saudi Arabia. Electronic address: moelbeeh@uqu.edu.sa.
⁷ Department of Pharmaceutics, Faculty of Pharmacy, Minia University, Minia 61519, Egypt; Department of Pharmaceutics, Faculty of Pharmacy, Umm Al-Qura University, Makkah 21955, Saudi Arabia.
⁸ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Horus University-Egypt, New Damietta 34518, Egypt; Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ahram Canadian University, 6th of October City, Giza 12566, Egypt. Electronic address: akarmalawy@horus.edu.eg.

PMID: 37678473
DOI: 10.1016/j.ijpharm.2023.123385

Abstract

The evolution of a safe and effective therapeutic system to conquer SAR-CoV-2 infection deemed to be a crucial worldwide demand. Curcumin (CUR) is a phytomedicinal polyphenolic drug that exhibited a well-reported anti-SAR-CoV-2. However, the therapeutic activity of CUR is hindered by its poor intestinal permeability and diminished aqueous solubility. Therefore, this study strived to develop D-alpha-tocopheryl polyethylene glycol succinate (TPGS) bilosomes (TPGS-Bs) adopting 2³ full factorial designs to improve solubility and intestinal permeability of CUR, hence boosting its anti-SARS-CoV-2 activity. Eight experimental runs were attained considering three independent variables: soybean phosphatidylcholine amount (mg) (SPC amount), bile salt amount (mg) (BS amount), and TPGS amount (mg). The optimum formula (F4) exhibited EE % (88.5 ± 2.4 %), PS (181.5 ± 21.6 nm), and ZP (-34.5 ± 3.7 mV) with desirability value = 0.739 was picked as an optimum formula. Furthermore, the optimum formula (F4) was extra coated with chitosan (CS) to improve permeability and anti-SAR-CoV-2 activity. Caco-2 cell uptake after 2 hr revealed the superiority of CS-F4 and F4 by 6 and 5 folds relative to CUR dispersion, respectively. Furthermore, CS-F4 exhibited a significantly higher anti-SARS-CoV-2 activity with IC₅₀ (0.24 µg/ml) by 8.3 times than F4 (1.99 µg/ml). Besides, the mechanistic study demonstrated that the two formulae imparted antiviral activity by inhibiting the spike protein by virucidal potentialities. In addition, the conducted molecular docking and MD simulations towards the SARS-CoV-2 M^pro enzyme confirmed the interaction of CUR with key residues of the virus enzymes. Based on the preceded, CS-F4 could be assumed to be used to effectively eradicate SARS-CoV-2 infection.

Keywords: Bilosomes; Caco-2 cell; Chitosan; In vitro mechanistic study; In-silico study; SARS-CoV-2; TPGS.