Effect of nanovesicular surface-functionalization via chitosan and/or PEGylation on cytotoxicity of tamoxifen in induced-breast cancer model

Mohamed A Megahed; Hossam S El-Sawy; Ahmed M Reda; Fathy I Abd-Allah; Sherif K Abu Elyazid; Ahmed E Lila; Hatem R Ismael; Khalid M El-Say

doi:10.1016/j.lfs.2022.120908

Effect of nanovesicular surface-functionalization via chitosan and/or PEGylation on cytotoxicity of tamoxifen in induced-breast cancer model

Life Sci. 2022 Oct 15:307:120908. doi: 10.1016/j.lfs.2022.120908. Epub 2022 Aug 24.

Authors

Mohamed A Megahed¹, Hossam S El-Sawy¹, Ahmed M Reda², Fathy I Abd-Allah³, Sherif K Abu Elyazid⁴, Ahmed E Lila⁴, Hatem R Ismael⁴, Khalid M El-Say⁵

Affiliations

¹ Department of Pharmaceutics and Pharmaceutical Technology, Egyptian Russian University, Cairo 11829, Egypt.
² Department of Biochemistry, Egyptian Russian University, Cairo 11829, Egypt.
³ Department of Pharmaceutics and Industrial Pharmacy, Al-Azhar University, Cairo 11651, Egypt; International Center for Bioavailability, Pharmaceutical and Clinical Research, Obour City 11828, Egypt.
⁴ Department of Pharmaceutics and Industrial Pharmacy, Al-Azhar University, Cairo 11651, Egypt.
⁵ Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia. Electronic address: kelsay1@kau.edu.sa.

PMID: 36028168
DOI: 10.1016/j.lfs.2022.120908

Abstract

Aims: The effect of surface-modification of Tamoxifen (Tam)-loaded-niosomes on drug cytotoxicity and bio-distribution, via functionalization with chitosan and/or PEGylation, was investigated.

Materials and methods: Tam-loaded hybrid-nanocarriers (Tam-loaded niosomes, chitosomes, PEGylated niosomes, and PEGylated chitosomes) were formulated and characterized.

Key findings: Chitosanization with/without PEGylation proved to selectively enhance Tam-release at the cancerous-acidic micromilieu. Cytotoxic activity study showed that Tam-loaded PEGylated niosomes had a lower IC₅₀ value on MCF-7 cell line (0.39, 0.35, and 0.27 times) than Tam-loaded PEGylated chitosomes, Tam-loaded niosomes, and Tam-loaded chitosomes, respectively. Cell cycle analysis showed that PEGylation and/or Chitosanization significantly impact Tam efficiency in inducing apoptosis, with a preferential influence of PEGylation over chitosanization. The assay of Annexin-V/PI double staining revealed that chitosanized-nanocarriers had a significant role in increasing the incidence of apoptosis over necrosis. Besides, PEGylated-nanocarriers increased apoptosis, as well as total death and necrosis percentages more than what was shown from free Tam. Moreover, the average changes in both Bax/Bcl-2 ratio and Caspase 9 were best improved in cells treated by Tam-loaded PEGylated niosomes over all other formulations. The in-vivo study involving DMBA-induced-breast cancer rats revealed that PEGylation made the highest tumor-growth inhibition (84.9 %) and breast tumor selectivity, while chitosanization had a lower accumulation tendency in the blood (62.3 ng/ml) and liver tissues (103.67 ng/ml). The histopathological specimens from the group treated with Tam-loaded PEGylated niosomes showed the best improvement over other formulations.

Significance: All these results concluded the crucial effect of both PEGylation and chitosan-functionalization of Tam-loaded niosomes in enhancing effectiveness, targetability, and safety.

Keywords: Apoptosis and necrosis detection; In-vitro/in-vivo correlation; Induced-breast cancer rats; Niosomes; Surface modification; Tamoxifen.

MeSH terms

Animals
Annexins
Apoptosis
Caspase 9
Chitosan* / pharmacology
Liposomes / pharmacology
Necrosis / drug therapy
Neoplasms* / drug therapy
Polyethylene Glycols / pharmacology
Rats
Tamoxifen / pharmacology
Tamoxifen / therapeutic use
bcl-2-Associated X Protein

Substances

Annexins
Liposomes
bcl-2-Associated X Protein
Tamoxifen
Polyethylene Glycols
Chitosan
Caspase 9