Lipid-Based Nanoparticle Formulation of Diallyl Trisulfide Chemosensitizes the Growth Inhibitory Activity of Doxorubicin in Colorectal Cancer Model: A Novel In Vitro, In Vivo and In Silico Analysis

Molecules

Arif Khan¹  Masood Alam Khan¹  Nahlah Makki Almansour²  Mahdi H. Alsugoor³  Ahmad A. Almatroudi⁴  Khloud Nawaf Alharbi⁴  Khaled S. Allemailem⁴  Faris Alrumaihi⁴  Ali Yousif Babiker⁴  Mohammed Alsaweed⁵  Faizul Azam⁶  Syed Rizwan Ahamad⁷ 

[1] Department of Basic Health Sciences, College of Applied Medical Sciences, Qassim University, Buraydah 51452, Saudi Arabia;Department of Biology, College of Science, University of Hafr Al Batin, Hafr Al Batin 31991, Saudi Arabia;Department of Emergency Medical Services, Faculty of Health Sciences, AlQunfudah, Umm Al-Qura University, Makkah 21912, Saudi Arabia;Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah 51452, Saudi Arabia;Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Majmaah University, Al-Majmaah 11952, Saudi Arabia;Department of Pharmaceutical Chemistry and Pharmacognosy, Unaizah College of Pharmacy, Qassim University, Unaizah 51911, Saudi Arabia;Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia;

关键词: diallyl trisulfide stealth liposomes;    doxorubicin PEGylated liposomes;    chemoprevention;    chemosensitization;    colorectal cancer;    molecular docking;   

DOI  :  10.3390/molecules27072192

来源: DOAJ

【 摘 要 】

Garlic’s main bioactive organosulfur component, diallyl trisulfide (DATS), has been widely investigated in cancer models. However, DATS is not suitable for clinical use due to its low solubility. The current study seeks to improve DATS bioavailability and assess its chemopreventive and chemosensitizing properties in an AOM-induced colorectal cancer model. The polyethylene glycol coated Distearoylphosphatidylcholine/Cholesterol (DSPC/Chol) comprising DATS-loaded DATSL and doxorubicin (DOXO)-encapsulated DOXL liposomes was prepared and characterized. The changes in the sensitivity of DATS and DOXO by DATSL and DOXL were evaluated in RKO and HT-29 colon cancer cells. The synergistic effect of DATSL and DOXL was studied by cell proliferation assay in the combinations of IC₁₀, IC₂₅, and IC₃₅ of DATSL with the IC₁₀ of DOXL. AOM, DATSL, and DOXL were administered to different groups of mice for a period of 21 weeks. The data exhibited ~93% and ~46% entrapment efficiency of DATSL and DOXL, respectively. The size of sham liposomes was 110.5 nm, whereas DATSL and DOXL were 135.5 nm and 169 nm, respectively. DATSL and DOXL exhibited significant sensitivity in the cell proliferation experiment, lowering their IC₅₀ doses by more than 8- and 14-fold, respectively. However, the DATSL IC₁₀, IC₂₅, and IC₃₅ showed escalating chemosensitivity, and treated the cells in combination with DOXL IC₁₀. Analysis of histopathological, cancer marker enzymes, and antioxidant enzymes revealed that the high dose of DATSL pretreatment and DOXL chemotherapy is highly effective in inhibiting AOM-induced colon cancer promotion. The combination of DATSL and DOXL indicated promise as a colorectal cancer treatment in this study. Intermolecular interactions of DATS and DOXO against numerous cancer targets by molecular docking indicated MMP-9 as the most favourable target for DATS exhibiting binding energy of −4.6 kcal/mol. So far, this is the first research to demonstrate the chemopreventive as well as chemosensitizing potential of DATSL in an animal model of colorectal cancer.

【 授权许可】

Unknown