Research Article

Novel delivery of sorafenib by natural killer cell-derived exosomes-enhanced apoptosis in triple-negative breast cancer

*Author for correspondence: Tel.: +98 218 887 6869;

E-mail Address: z.hashemi@acecr.ac.ir

https://orcid.org/0000-0001-6353-987X

ATMP Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, 15179/64311, Iran

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Mahlegha Ghavami

Pathology Department, Dalhousie University, Halifax, B3H 4R2, Canada

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Seyed Hossein Kiaie

Student Research Committee, Tabriz University of Medical Sciences, Tabriz, 5166614711, Iran

Nano Drug Delivery Research Center, Kermanshah University of Medical Sciences, Kermanshah, 6715847141, Iran

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Fateme Mohammadi

Department of Hematology, School of Allied Medical Sciences, Tehran University of Medical Sciences, Tehran, 1417653761, Iran

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Mahdieh Shokrollahi Barough

ATMP Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, 15179/64311, Iran

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Saeed Khalili

https://orcid.org/0000-0003-0493-9595

Department of Biology Sciences, Shahid Rajaee Teacher Training University, Tehran, 167815811, Iran

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Zahra Hosseini-Farjam

ATMP Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, 15179/64311, Iran

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Majid Mossahebi-Mohammadi

School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325027, China

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Alireza Sheidary

Department of Pharmaceutical Nanotechnology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, 1417653761, Iran

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Ardeshir Ghavamzadeh

Cancer & Cell Therapy Research Center, Tehran University of Medical Sciences, Tehran, 1417653761, Iran

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Ramin Sarrami Forooshani

**Author for correspondence: Tel.: +98 218 887 6869;

E-mail Address: sarrami@acecr.ac.ir

https://orcid.org/0000-0002-6999-9145

ATMP Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, 15179/64311, Iran

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Published Online:18 May 2023https://doi.org/10.2217/nnm-2022-0237

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Abstract

Aim: We investigated the delivery of sorafenib (SFB) to breast cancer spheroids by natural killer cell-derived exosomes (NK-Exos). Methods: SFB-NK-Exos were constructed by electroporation. Their antitumor effects were evaluated by methyl thiazolyl tetrazolium, acridine orange/ethidium bromide, 4′,6-diamidino-2-phenylindole, annexin/propidium iodide, scratch and migration assay, colony formation, RT-PCR, western blot and lipophagy tests. Result: The loading efficacy was 46.66%. SFB-NK-Exos-treated spheroids showed higher cytotoxic effects (33%) and apoptotic population (44.9%). Despite the reduction of SFB concentration in the SFB-NK-Exos formulation, similar cytotoxic effects to those of free SFB were observed. Increased intracellular trafficking, sustained release of the drug and selective inhibitory effects demonstrated efficient navigation. Conclusion: This is the first report for SFB loading into NK-Exos, which led to significant cytotoxic intensification against cancer cells.

Plain language summary

What is this summary about?

This study describes the delivery of an anticancer drug called sorafenib (SFB) to laboratory-grown spherical masses of cancer cells called spheroids. Saucer-like cellular structures called exosomes were used as drug-delivery tools. These exosomes were produced by a subgroup of immune cells called natural killer (NK) cells. NK cells are responsible for killing cancer cells. So, these exosomes share similar anticancer properties with NK cells. We wanted to test whether exosomes loaded with SFB would have better anticancer effects.

What were the results?

Using different methods, SFB was loaded within the exosomes and delivered to the spheroids. The obtained results showed that a combination of exosomes and SFB could improve the targeting efficacy, reducing the side effects to the normal cells and allowing continuous release of the drug. The spheroids were killed with higher efficacy following this treatment.

What do the results of the study mean?

The combination of NK cell-derived exosomes and SFB could lead to better cytotoxicity against cancer cells. Therefore, this strategy could have better anticancer effects compared with SFB treatment alone.

Keywords:

Papers of special note have been highlighted as: • of interest; •• of considerable interest

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Vol. 18, No. 5

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History

Received 10 September 2022

Accepted 13 March 2023

Published online 18 May 2023

Published in print February 2023

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Keywords

Acknowledgments

The authors wish to thank the Motamed Cancer Institute for their support to conduct this study.

Financial & competing interests disclosure

The authors have no relevant affiliations or 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.

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

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

Data availability statement

The data generated during the study to support the findings are available upon request from the corresponding authors (Z Hashemi and R Sarrami Forooshani) upon reasonable request.

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