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Glycol chitosan stabilized nanomedicine of lapatinib and doxorubicin for the management of metastatic breast tumor

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Abstract

Advanced breast cancer is known to be highly evasive to conventional therapeutic regimes with a 5-year survival rate of less than 30% compared to over 90% for early stages. Although several new approaches are being explored to improve the survival outcome, there is still some room for equipping existing drugs such as lapatinib (LAPA) and doxorubicin (DOX) to fight the systemic disease. LAPA is associated with poorer clinical outcomes in HER2-negative patients. However its ability to also target EGFR has warranted its use in recent clinical trials. Nevertheless, the drug is poorly absorbed post oral administration and possess low aqueous solubility. DOX on the other hand is avoided in vulnerable patients in advanced stages due to its pronounced off-target toxicity. To overcome the pitfalls of the drugs, we have fabricated a nanomedicine co-loaded with LAPA & DOX and stabilized with glycol chitosan, a biocompatible polyelectrolyte. With a loading content of ~ 11.5% and ~ 15% respectively, LAPA and DOX in a single nanomedicine showed synergistic action against triple-negative breast cancer cells in comparison to physically mixed free drugs. The nanomedicine showed a time-dependent association with cancer cells thereon inducing apoptosis leading to ~ 80% cell death. The nanomedicine was found to be acutely safe in healthy Balb/c mice and could negate DOX-induced cardio toxicity. The combination nanomedicine significantly inhibited both the primary 4T1 breast tumor and its spread to the lung, liver, heart, and kidney compared to pristine drug controls. These preliminary data indicate bright prospects for the nanomedicine to be effective against metastatic breast cancer.

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The datasets generated during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

Navneet Kaur and Priyanka Sharma would like to thank the Institute of Nano Science and Technology for senior research fellowships. Mimansa acknowledges the University Grants Commission for senior research fellowship. The authors acknowledge Dr. Nitin Singhal and Ms. Poonam Sagar for helping with IVIS studies at the National Agri Food Biotechnology Institute. Asifkhan Shanavas remembers the late Ms. Shajereth Begum for her brave encounter with metastatic breast cancer.

Funding

Dr. Asifkhan Shanavas received funding from the Government of India under the SERB core research grant scheme (EMR/2016/003851).

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Author notes

  1. Navneet Kaur and Priyanka Sharma contributed equally to this work.

Authors and Affiliations

  1. Inorganic & Organic Nanomedicine Lab, Chemical Biology Unit, Institute of Nano Science and Technology, Sector-81, Knowledge City, Sahibzada Ajit Singh Nagar, Punjab, 140306, India

    Navneet Kaur, Priyanka Sharma,  Mimansa, Mahendran Jaganathan & Asifkhan Shanavas

  2. Department of Anatomy, Post Graduate Institute of Medical Education and Research, Madhya Marg, Sector 12, Chandigarh, 160012, India

    Rafika Munawara & Anjali Aggarwal

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Contributions

Navneet Kaur: methodology, writing—original draft, visualization, formal analysis, investigation. Priyanka: writing—methodology, visualization, investigation. Mimansa: methodology, investigation. Mahendran Jaganathan: visualization, investigation. Rafika Munawara: methodology, formal analysis. Anjali Aggarwal: methodology, formal analysis. Asifkhan Shanavas: conceptualization, project administration, supervision, resources, writing—review & editing, funding acquisition.

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Correspondence to Asifkhan Shanavas.

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Kaur, N., Sharma, P., Mimansa et al. Glycol chitosan stabilized nanomedicine of lapatinib and doxorubicin for the management of metastatic breast tumor. Drug Deliv. and Transl. Res. 13, 2520–2532 (2023). https://doi.org/10.1007/s13346-023-01335-6

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