Theranostics 2023; 13(9):2800-2810. doi:10.7150/thno.81834 This issue Cite

Research Paper

Nanoblock-mediated selective oncolytic polypeptide therapy for triple-negative breast cancer

Cuiyu Zhong1,6#, Jie Li5#, Suiping Liu1,2,4, Weirong Li1,2, Qiang Zhang7, Junpeng Zhao7, Menghua Xiong5✉, Yan Bao2,4✉, Yandan Yao1,2,3✉

1. Breast Tumor Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China.
2. Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China.
3. Shenshan Medical Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Shanwei 516621, China.
4. Nanhai Translational Innovation Center of Precision Immunology, Sun Yat-Sen Memorial Hospital, Foshan 528200, China.
5. School of Biomedical Sciences and Engineering, South China University of Technology, Guangzhou International Campus, Guangzhou, 511442, China.
6. The Third Affiliated Hospital, Guangzhou Medical University, Guangzhou 510150, China.
7. Faculty of Materials Science and Engineering, South China University of Technology, Guangzhou, 510640, China.
# These authors contribute equally.

Citation:
Zhong C, Li J, Liu S, Li W, Zhang Q, Zhao J, Xiong M, Bao Y, Yao Y. Nanoblock-mediated selective oncolytic polypeptide therapy for triple-negative breast cancer. Theranostics 2023; 13(9):2800-2810. doi:10.7150/thno.81834. https://www.thno.org/v13p2800.htm
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Abstract

Graphic abstract

Rationale: Broad-spectrum oncolytic peptides (Olps) constitute potential therapeutic options for treating heterogeneous triple-negative breast cancer (TNBC); however, their clinical application is limited owing to high toxicity.

Methods: A nanoblock-mediated strategy was developed to induce selective anticancer activity of synthetic Olps. A synthetic Olp, C12-PButLG-CA, was conjugated to the hydrophobic or hydrophilic terminal of a poly(ethylene oxide)-b-poly(propylene oxide) nanoparticle or a hydrophilic poly(ethylene oxide) polymer. A nanoblocker, that can significantly reduce the toxicity of Olp, was screened out through hemolytic assay, and then Olps were conjugated to the nanoblock via a tumor acidity-cleavable bond to obtain the selective RNolp ((mPEO-PPO-CDM)2-Olp). The tumor acidity responsive membranolytic activity, in vivo toxicity and anti-tumor efficacy of RNolp were determined.

Results: We found that the conjugation of Olps to the hydrophobic core of a nanoparticle but not the hydrophilic terminal or a hydrophilic polymer restricts their motion and drastically reduces their hemolytic activity. We then covalently conjugated Olps to such a nanoblock via a cleavable bond that can be hydrolyzed in the acidic tumor environment, yielding a selective RNolp molecule. At physiological pH (pH 7.4), RNolp remained stable with the Olps shielded by nanoblocks and exhibited low membranolytic activity. At the acidic tumor environment (pH 6.8), Olps could be released from the nanoparticles via the hydrolysis of the tumor acidity-cleavable bonds and exerted membranolytic activity against TNBC cells. RNolp is well tolerated in mice and demonstrated high antitumor efficacy in orthotopic and metastatic mouse models of TNBC.

Conclusion: We developed a simple nanoblock-mediated strategy to induce a selective cancer therapy of Olps for TNBC.

Keywords: Oncolytic polypeptides, Triple-negative breast cancer, Tumor microenvironment, pH responsiveness


Citation styles

APA
Zhong, C., Li, J., Liu, S., Li, W., Zhang, Q., Zhao, J., Xiong, M., Bao, Y., Yao, Y. (2023). Nanoblock-mediated selective oncolytic polypeptide therapy for triple-negative breast cancer. Theranostics, 13(9), 2800-2810. https://doi.org/10.7150/thno.81834.

ACS
Zhong, C.; Li, J.; Liu, S.; Li, W.; Zhang, Q.; Zhao, J.; Xiong, M.; Bao, Y.; Yao, Y. Nanoblock-mediated selective oncolytic polypeptide therapy for triple-negative breast cancer. Theranostics 2023, 13 (9), 2800-2810. DOI: 10.7150/thno.81834.

NLM
Zhong C, Li J, Liu S, Li W, Zhang Q, Zhao J, Xiong M, Bao Y, Yao Y. Nanoblock-mediated selective oncolytic polypeptide therapy for triple-negative breast cancer. Theranostics 2023; 13(9):2800-2810. doi:10.7150/thno.81834. https://www.thno.org/v13p2800.htm

CSE
Zhong C, Li J, Liu S, Li W, Zhang Q, Zhao J, Xiong M, Bao Y, Yao Y. 2023. Nanoblock-mediated selective oncolytic polypeptide therapy for triple-negative breast cancer. Theranostics. 13(9):2800-2810.

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