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Selective COX-2 Inhibitor Etoricoxib’s Liposomal Formulation Attenuates M2 Polarization of TAMs and Enhances its Anti-metastatic Potential

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Abstract

Introduction

COX-2 inhibition in pro-tumoral M2 polarization of Tumor-Associated Macrophages (TAMs) underscore the improved prognosis and response to cancer therapy. Thus, etoricoxib, a COX-2 inhibiting NSAID drug is highly effective against tumorigenesis, but its compromised solubility and associated hepatotoxicity, and cardiotoxicity limit its clinical translation.

Objective

In view of the consequences, the proposed study entails the development of a liposomal formulation for etoricoxib and evaluates its anticancer potential.

Methods and Result

Etoricoxib loaded liposome was prepared by thin layer hydration method and characterized as a nearly monodisperse system with particle size (91.64 nm), zeta potential (-44.5 mV), drug loading (17.22%), and entrapment efficiency (94.76%). The developed formulation was administered subcutaneously into the orthotopic 4T1/Balb/c mice model. Its treatment significantly reduced tumor size and skewed M2 polarization of TAMs to a greater extent against free etoricoxib. Furthermore, Tumor tissues analyzed through immunoblotting study confirmed the reduction in Akt phosphorylation at Thr308 residue and pro-tumoral VEGF, MMP-9, and MMP-2 proteins; Moreover, histology studies and microCT analysis of bones revealed the enhanced anti-metastatic potential of etoricoxib delivered through developed formulation against free etoricoxib.

Conclusion

As an epilogue, the developed formulation efficiently delivers poorly soluble etoricoxib, enhances its therapeutic potential as an anti-tumor and anti-metastatic agent, and directs explorative research for clinical translation.

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Data Availability

The datasets used and/or analysed in the course of the present study are available from the corresponding author on reasonable request.

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Acknowledgements

We are thankful to the Director of CSIR-CDRI for providing the facility/infrastructure support. We extend our thanks to Mr. Anurag Kumar Srivastava for the biochemistry analysis of serum. We are highly thankful to Dr. Kalyan Mitra and Ms. Garima Pant for facilitating Transmission Electron Microscopy. The CSIR-CDRI communication number allotted to this manuscript is 10534. 

Funding

This work was supported by a grant from the Council of Science and Technology, Uttar Pradesh (CST/8380/2018, GAP0277) and a CDRI in-house project.

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  1. Usmani Mohammed Akif and Javed Miyan contributed equally to this work.

Authors and Affiliations

  1. Division of Toxicology and Experimental Medicine, CSIR-Central Drug Research Institute (CDRI), Lucknow, Uttar Pradesh, 226031, India

    Usmani Mohammed Akif, Javed Miyan,  Moinuddin, Narayan Kumar Goswami,  Tanzeela & Smrati Bhadauria

  2. Academy of Scientific & Innovative Research (AcSIR), Ghaziabad, 201002, India

    Usmani Mohammed Akif, Javed Miyan,  Moinuddin, Narayan Kumar Goswami,  Tanzeela, Smrati Bhadauria & Manish Kumar Chourasia

  3. Division of Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute (CDRI), Lucknow, Uttar Pradesh, 226031, India

    Rafquat Rana & Manish Kumar Chourasia

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Contributions

Smrati Bhadauria conceptualized, planned biological experiments, and interpreted the data, Manish Kumar Chourasia was involved in the conception, design, analysis, and interpretation of formulation data. Usmani Mohammed Akif performed all in vivo, immunohistochemistry, immunoblotting, toxicity study, microCT analysis, and statistical analysis of the study. Javed Miyan was involved in in vivo study, Rafquat Rana was involved in the preparation of etoricoxib liposomal formulation and its characterization, Moinuddin did immunohistochemistry. Narayan Kumar Goswami helped in microCT analysis, Tanzeela performed H&E. Smrati Bhadauria, Usmani Mohammed Akif, and Rafquat Rana were involved in the writing of the manuscript. Usmani Mohammed Akif and Javed Miyan contributed equally to this work.

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Akif, U.M., Miyan, J., Rana, R. et al. Selective COX-2 Inhibitor Etoricoxib’s Liposomal Formulation Attenuates M2 Polarization of TAMs and Enhances its Anti-metastatic Potential. Pharm Res 40, 551–566 (2023). https://doi.org/10.1007/s11095-022-03444-2

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