In vivo evaluation of mebendazole and Ran GTPase inhibition in breast cancer model system

Abstract

Aim: To investigate the therapeutic potential of mebendazole (MBZ)-loaded nanostructured lipid carriers (NLCs). Methodology: NLC-MBZ was prepared and characterized to evaluate the in vitro and in vivo anticancer effects and the inhibitory effect on RanGTP and its potential as an antimetastatic treatment in vivo. Results: NLC-MBZ exhibited a size and charge of 155 ± 20 nm and -27 ± 0.5 mV, respectively, with 90.7% encapsulation. Free MBZ and NLC-MBZ had a 50% inhibitory concentration of 610 and 305 nM, respectively, against MDA-MB-231 cell lines. NLC-MBZ decreased tumor size, suppressed tumor lung metastases, and lowered the expression of CDC25A, SKP2, RbX1 and Cullin1 while boosting the Rb proteins. Conclusion: NLC-MBZ displayed antiangiogenic potential and resulted in a reduced rate of lung metastasis in vivo.

Graphical abstract

Summary points

• In this study, we developed and characterized nanostructured lipid carriers (NLCs) loaded with mebendazole (MBZ; NLC-MBZ).

• NLC-MBZ was prepared to investigate its in vitro and in vivo anticancer effects.

• NLC-MBZ was explored for its inhibitory impact on RanGTP and its potential as an antimetastatic agent in mouse models.

• NLC-MBZ displayed a size of 155 ± 20 nm with a -27 ± 0.5-mV charge and 90.7% encapsulation efficiency.

• After 48 h of exposure, the IC₅₀ for free MBZ and NLC-MBZ was 610 and 305 nM, respectively, against MDA-MB-231 breast cancer cell lines.

• Moreover, NLC-MBZ reduced the size of the primary tumor and inhibited the development of lung metastases.

• NLC-MBZ reduced the expression CDC25A, SKP2, RbX1 and Cullin1 while increasing the expression of Rb proteins.

• NLC-MBZ showed antiangiogenic potential that resulted in a reduced rate of lung metastasis in vivo.

Keywords: :

• angiogenesis
• animal model
• breast cancer
• mebendazole
• metastases
• nanostructured lipid carriers
• oleic acid
• Ran GTP
• RT-PCR
• stearic acid

Author contributions

B Abu-Hdaib and H Nsairat wrote the research proposal and designed the preparation and characterization experiments along with writing the first draft of the manuscript. M El-Tanani, I Al-deeb and N Hasasna performed the in vitro and in vivo assays and revised the final manuscript draft.

Financial disclosure

The authors have no financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Competing interests disclosure

The authors have no competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Writing disclosure

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

Animal experiments were conducted in strict accordance with ethical standards and received approval from the institutional review board (IRB) and ethical issues committee of Al-Ahliyya Amman University (IRB no.: AAU/2/6/2022-2023), which adheres to Helsinki Declaration 21 and 23 protocols of the Scientific Requirements and Research Protocols and Research Ethics Committees.