Self-Nanoemulsifying Drug Delivery System of 2-Methoxyestradiol Exhibits Enhanced Anti-Proliferative and Pro-Apoptotic Activities in MCF-7 Breast Cancer Cells

  • Life (Basel). 2022 Sep 2;12(9):1369. doi: 10.3390/life12091369.
Salwa D Al-Qahtani  1  2 ,  Hawazen H Bin-Melaih  3 ,  Eman M Atiya  2 ,  Usama A Fahmy  4 ,  Lenah S Binmahfouz  5 ,  Thikryat Neamatallah  5 ,  Fahad A Al-Abbasi  2 ,  Ashraf B Abdel-Naim  5
Affiliations
  • 1. Department of Medical Laboratory Sciences, Faculty of Applied Medical Science, Majmaah University, Majmaah 11952, Saudi Arabia.
  • 2. Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia.
  • 3. Department of Biological Sciences, Faculty of Sciences, King Abdulaziz University, Jeddah 21589, Saudi Arabia.
  • 4. Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia.
  • 5. Department of Pharmacology and Toxicology, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia.
PMID: 36143405 DOI: 10.3390/life12091369
Abstract

(1) Background: 2-Methoxyestradiol (2ME) is a metabolite of estrogens and possesses promising anti-proliferative and cytotoxic activities. However, it suffers unfavorable pharmacokinetic characteristics such as absorption after oral administration. The aim of this study was to prepare an optimized 2ME self-nanoemulsifying drug delivery system (2ME-SNEDDS) and evaluate its cytotoxicity and pro-apoptotic activities in MCF-7 breast Cancer cells. (2) Methods: For optimization of the 2ME-SNEDDS, a three-component system was used in the D-optimal mixture experimental study. MCF-7 cells were incubated with the 2ME-SNEDDS and subjected to an assessment of growth inhibition, cell cycle progression, annexin V staining, Caspase-3 concentration, Bax, Bcl-2, and cyclin D1 mRNA expression, and Reactive Oxygen Species (ROS) generation. (3) Results: The optimized formula had a globule size of 94.97 ± 4.35 nm. Zeta potential was found to be -3.4 ± 1.2 mV with a polydispersity index (PDI) of 0.34. In addition, 96.3 ± 4.3% of 2ME was released from the 2ME-SNEDDS within 24 h using the activated analysis bag technique. Moreover, the prepared 2ME-SNEDDS exhibited a significant enhancement of the anti-proliferative activity against MCF-7 cells in comparison to raw 2ME. This was associated with cyclin D1 expression down-regulation and the accumulation of cells in the G0/G1 and G2/M phases. The pro-apoptotic activities of the 2ME-SNEDDS were confirmed by annexin V staining, which indicated enhanced early and late cell death. This accompanied modulation of the mRNA expression of Bax and Bcl-2 in favor of Apoptosis. The 2ME-SNEDDS significantly enhanced cleaved Caspase-3 concentration in comparison to raw 2ME. In addition, the 2ME-SNEDDS significantly increased the generation of ROS in MCF-7 cells. (4) Conclusions: The 2ME-SNEDDS exhibits enhanced cytotoxicity and pro-apoptotic activity in MCF-7 cells. This is mediated by, at least partially, ROS generation.

Keywords
2-methoxyestradiol; apoptosis; breast cancer cells; cytotoxicity; self-nanoemulsifying drug delivery system.
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