Ameliorating the antitumor activity of gemcitabine against breast tumor using α_vβ₃ integrin-targeting lipid nanoparticles

Abstract

Objective

The main objective is to formulate solid lipid nanoparticles conjugated with cyclic RGDfk peptide encapsulated with gemcitabine hydrochloride drug for targeting breast cancer.

Significance

The hydrophilic nature of gemcitabine hampers passive transport by cell membrane permeation that may lead to drug resistance as it has to enter the cells via nucleoside transporters. The art of encapsulating the drug in a nanovesicle and then anchoring it with a targeting ligand is one of the present areas of research in cancer chemotherapy.

Methods

In this study, solid lipid nanoparticles were prepared by double emulsification and solvent evaporation method. Cyclic RGDfk and gemcitabine hydrochloride were used as targeting ligands and chemotherapeutic drugs, respectively, for targeting breast cancer. The prepared nanoparticles were evaluated for in vitro and in vivo performance to showcase the targeting efficiency and therapeutic benefits of the gemcitabine-loaded ligand conjugated nanoparticles.

Results

When compared with gemcitabine (GEM) and GEM loaded nanoparticles (GSLN), the ligand conjugated GEM nanoparticles (cGSLN) showed superior cytotoxicity, apoptosis, and inhibition of 3D multicellular spheroids in human breast cancer cells (MDA MB 231). The in vivo tumor regression studies in orthotopic breast cancer induced Balb/C mice showed that cGSLN displayed superior tumor suppression and also the targeting potential of the cGSLN toward induced breast cancer.

Conclusion

Prepared nanoformulations showed enhanced anticancer activity in both 2D and 3D cell culture models along with antitumor efficacy in orthotopic breast cancer mouse models.

Graphical Abstract

Keywords:

• cRGDfK
• integrin receptors
• solid lipid nanoparticles
• gemcitabine
• breast cancer
• targeted drug delivery

Acknowledgments

The authors thank the Director, CSIR-Indian Institute of Chemical Technology, Hyderabad and RMIT University, Australia for providing the necessary facilities and support. This work was performed in part at the RMIT Micro Nano Research Facility (MNRF) in the Victorian Node of the Australian National Fabrication Facility (ANFF). The authors are grateful to M/s Therdose Pharma for providing gemcitabine hydrochloride as a gift sample.

Author contributions

The manuscript was written with the contributions of all authors. All authors have approved the final version of the manuscript.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

HK acknowledges Central Instrumentation Facility, Central University of Gujarat, Gandhinagar. He also acknowledges the Department of Science and Technology, New Delhi for INSPIRE Faculty Award (DST/INSPIRE/04/2015/000594). LT acknowledges IICT-RMIT Research Centre for providing Ph.D. scholarships. IICT manuscript communication number is IICT/Pubs./2021/161. This work was financially supported by RMIT University, Australia and CSIR-IICT, Hyderabad, India.