Nanofabrications of Erythrocyte Membrane-Coated Telmisartan Delivery System Effective for Radiosensitivity of Tumor Cells in Mice Model

Abstract

Background

Radiation stimulates the secretion of tumor stroma and induces resistance, recurrence, and metastasis of stromal-vascular tumors during radiotherapy. The proliferation and activation of tumor-associated fibroblasts (TAFs) are important reasons for the production of tumor stroma. Telmisartan (Tel) can inhibit the proliferation and activation of TAFs (resting TAFs), which may promote radiosensitization. However, Tel has a poor water solubility.

Methods

In this study, self-assembled telmisartan nanoparticles (Tel NPs) were prepared by aqueous solvent diffusion method to solve the insoluble problem of Tel and achieve high drug loading of Tel. Then, erythrocyte membrane (ECM) obtained by hypotonic lysis was coated on the surface of Tel NPs (ECM/Tel) for the achievement of in vivo long circulation and tumor targeting. Immunofluorescence staining, western blot and other biological techniques were used to investigate the effect of ECM/Tel on TAFs activation inhibition (resting effect) and mechanisms involved. The multicellular spheroids (MCSs) model and mouse breast cancer cells (4T1) were constructed to investigate the effect of ECM/Tel on reducing stroma secretion, alleviating hypoxia, and the corresponding promoting radiosensitization effect in vitro. A mouse orthotopic 4T1 breast cancer model was constructed to investigate the radiosensitizing effect of ECM/Tel on inhibiting breast cancer growth and lung metastasis of breast cancer.

Results

ECM/Tel showed good physiological stability and tumor-targeting ability. ECM/Tel could rest TAFs and reduce stroma secretion, alleviate hypoxia, and enhance penetration in tumor microenvironment. In addition, ECM/Tel arrested the cell cycle of 4T1 cells to the radiosensitive G2/M phase. In mouse orthotopic 4T1 breast cancer model, ECM/Tel played a superior role in radiosensitization and significantly inhibited lung metastasis of breast cancer.

Conclusion

ECM/Tel showed synergistical radiosensitization effect on both the tumor microenvironment and tumor cells, which is a promising radiosensitizer in the radiotherapy of stroma-vascular tumors.

Keywords:

• telmisartan
• tumor-associated fibroblasts
• tumor hypoxia
• G2/M arrest
• radiosensitization

Data Sharing Statement

All materials and data supporting this study are available from the author ([email protected]) upon reasonable request.

Acknowledgments

This work has been supported by National Natural Science Foundation of China (Grant No. 81871756 and No. 82303692), Jiangsu Provincial Outstanding Postdoctoral Program (No. 2022ZB824), the Fourth Batch of City Leading Innovative Talents Introduction and Cultivation Project of Changzhou “Dragon City Talent Plan” (Research No. CQ20220107), Science and Technology Project of Changzhou Health Commission (Science and Technology Project for Young Talents) (Research No. QN202224), Basic Research Project of Changzhou Medical Center of Nanjing Medical University (CMCB202231), Innovation Fund of National Orthopedics and Exercise Rehabilitation Clinical Medical Research Center (Research No. 2021-NCRC-CXJJ-ZH-13), Jiangsu Provincial Medical Key Discipline Cultivation Unit (JSDW202237), Jiangsu Provincial Key Research and Development Program Social Development Project (BE2022720), General Program of Jiangsu Provincial Health Commission (M2020006).

Disclosure

The authors declare that they have no competing interests for this work.