Research Article

Engineering extracellular vesicles mimetics for targeted chemotherapy of drug-resistant ovary cancer

Department of Gynecology, Women's Hospital of Nanjing Medical University, Nanjing Maternity & Child Health Care Hospital, Nanjing, 210001, China

‡Authors contributed equally

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Guangquan Liu‡

Department of Gynecology, Women's Hospital of Nanjing Medical University, Nanjing Maternity & Child Health Care Hospital, Nanjing, 210001, China

‡Authors contributed equally

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Yinghua Mao‡

Centre for Diseases Prevention & Control of Eastern Theater, Nanjing, 210002, China

‡Authors contributed equally

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Jie Luo

Department of Healthcare, General Hospital of Eastern Theater Command, Nanjing, 210002, China

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Yongping Cao

Centre for Diseases Prevention & Control of Eastern Theater, Nanjing, 210002, China

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Weilong Tan

Centre for Diseases Prevention & Control of Eastern Theater, Nanjing, 210002, China

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Wenhao Li

Centre for Diseases Prevention & Control of Eastern Theater, Nanjing, 210002, China

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Huanhuan Yu

Department of Clinical Pharmacy, General Hospital of Eastern Theater Command, Nanjing, 210002, China

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Xuemei Jia

**Author for correspondence:

E-mail Address: xmjia@njmu.edu.cn

Department of Gynecology, Women's Hospital of Nanjing Medical University, Nanjing Maternity & Child Health Care Hospital, Nanjing, 210001, China

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Hong Li

*Author for correspondence: Tel.: +86 199 5176 6830;

E-mail Address: lihong0708@sina.com

https://orcid.org/0000-0002-4091-8356

Centre for Diseases Prevention & Control of Eastern Theater, Nanjing, 210002, China

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Published Online:7 Dec 2023https://doi.org/10.2217/nnm-2023-0289

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Abstract

Aim: To develop nanocarriers for targeting the delivery of chemotherapeutics to overcome multidrug-resistant ovarian cancer. Materials & methods: Doxorubicin-loaded nanovesicles were obtained through serial extrusion, followed by loading of P-glycoprotein siRNA and folic acid. The targeting ability and anticancer efficacy of the nanovesicles were evaluated. Results: The doxorubicin-loaded nanovesicles showed a high production yield. The presence of P-glycoprotein siRNA and folic acid resulted in reversed drug resistance and tumor targeting. This nanoplatform tremendously inhibited the viability of multidrug-resistant ovarian cancer cells, which was able to target tumor tissue and suppress tumor growth without adverse effects. Conclusion: These bioengineered nanovesicles could serve as novel extracellular vesicles mimetics for chemotherapeutics delivery to overcome multidrug resistance.

Plain language summary

When treating cancer affecting the ovaries, which is an organ in the female reproductive system, two challenges that arise are the inefficient delivery of chemotherapeutic drugs and the development of drug resistance inside the tumor. In this study, very small nano-scale particles called nanovesicles, which contain a chemotherapeutic drug called doxorubicin, were developed in an attempt to overcome both of these concerns. These nanovesicles were secreted by a healthy cell from an ovary, isolated and loaded with doxorubicin. These nanovesicles were also loaded with siRNA, which, in this case, prevents the synthesis of a protein in ovarian tumor cells called P-glycoprotein. This protein is responsible for pumping chemotherapy drugs back out of tumor cells, so preventing its synthesis was intended to counter chemotherapeutic resistance. The targeting ability of the nanovesicle was also enhanced with folic acid, as folic acid receptors are present on the surface of these tumor cells in higher numbers. These nanovesicles were readily and specifically taken up by ovarian tumor cells in mice with induced ovarian cancer. This reversed drug resistance and enhanced the toxic effects of doxorubicin on the tumor cells, which, in turn, increased tumor cell death and prevented tumor cell migration. No obvious adverse effect was found in mice treated with the nanovesicle system compared with the free chemotherapy drug with critical systematic toxicity. This research provides new avenues for ovarian cancer treatment, with combined therapies of siRNAs and chemotherapeutic drugs, targeted to tumor cells specifically, within nanovesicles.

Tweetable abstract

Doxorubicin-loaded extracellular vesicles-mimetic nanovesicles were developed by the extrusion method, followed by siRNA loading and targeted modification, resulting in effective delivery of chemotherapeutics to overcome drug resistance of ovarian cancer.

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Vol. 19, No. 1

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History

Received 9 October 2023

Accepted 9 November 2023

Published online 7 December 2023

Published in print January 2024

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Keywords

Supplementary data

To view the supplementary data that accompany this paper please visit the journal website at: www.futuremedicine.com/doi/suppl/10.2217/nnm-2023-0289

Author contributions

XG Liu performed the major experiments, generated data and analyzed data. GQ Liu designed the experiment and drafted the manuscript. YH Mao and J Luo performed the experiment. YP Cao, WH Li and HH Yu helped with manuscript editing. XM Jia reviewed the manuscript drafts. H Li designed and supervised the overall experiment and wrote the manuscript. All authors read and approved the final manuscript.

Acknowledgments

The authors thank J Xu for gifting the human multidrug resistant ovarian cancer A2780/MDR cells.

Financial disclosure

This work was supported by grants from the National Natural Science Foundation of China (no. 81803173, 81901555 and 81971351) and the Social Development Project of Jiangsu Province (no. BE2022682). The authors have no other 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 apart from those disclosed.

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

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 animal experimental investigations. All animals were used as per the guidelines approved by the Animal Welfare and Research Ethics Committee of Centre for Diseases Prevention and Control of Eastern Theater.

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