A Prodrug Nanodevice Co-delivering Docetaxel and ROR1 siRNA for Enhanced Triple Negative Breast Cancer Therapy

Lixuan Yin; Zirang Fu; Mengmeng Wang; Bo Liu; Xujie Sun; Kaiyue Liu; Xiaolong Feng; Zongyan He; Yutong Wang; Jiazhen Hou; Xinyue Shao; Ning Yang; Tian Zhang; Yiran Liu; Zhengwei Huang; Qi Yin; Yuanchao Xie; Yaping Li; Tianqun Lang

doi:10.1016/j.actbio.2024.12.055

A Prodrug Nanodevice Co-delivering Docetaxel and ROR1 siRNA for Enhanced Triple Negative Breast Cancer Therapy

Acta Biomater. 2024 Dec 25:S1742-7061(24)00776-1. doi: 10.1016/j.actbio.2024.12.055. Online ahead of print.

Authors

Lixuan Yin¹, Zirang Fu², Mengmeng Wang³, Bo Liu⁴, Xujie Sun¹, Kaiyue Liu¹, Xiaolong Feng⁵, Zongyan He², Yutong Wang², Jiazhen Hou², Xinyue Shao⁶, Ning Yang², Tian Zhang², Yiran Liu², Zhengwei Huang⁷, Qi Yin³, Yuanchao Xie², Yaping Li⁸, Tianqun Lang⁹

Affiliations

¹ Lingang Laboratory, Shanghai 200031, China; State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
² Lingang Laboratory, Shanghai 200031, China.
³ State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
⁴ Biological Sciences Division, Department of Medicine, Section of Genetic Medicine, University of Chicago, Chicago, Illinois 60637, United States.
⁵ Lingang Laboratory, Shanghai 200031, China; School of Pharmacy, East China Normal University, Shanghai 200062, China.
⁶ Lingang Laboratory, Shanghai 200031, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
⁷ State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, College of Pharmacy, Jinan University, Guangzhou 511436, China.
⁸ State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: ypli@simm.ac.cn.
⁹ Lingang Laboratory, Shanghai 200031, China. Electronic address: langtq@lglab.ac.cn.

PMID: 39730101
DOI: 10.1016/j.actbio.2024.12.055

Abstract

Triple-negative breast cancer (TNBC) has been a clinical challenge due to its high recurrence and metastasis rates. Chemotherapy remains the primary treatment for TNBC after surgery ablation, but it lacks targeted specificity and causes side effects in normal tissues. Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is significantly expressed in TNBC cells, and small interference RNA (siRNA) targeting ROR1 can effectively suppress ROR1 gene expression, thereby inhibiting proliferation and metastasis. However, clinical application of ROR1 siRNA is limited by susceptibility to clearance and difficulty in endosomal escape. In this study, the docetaxel (DTX) prodrug nanoparticle BBRM delivering ROR1 siRNA was constructed. The BBRM could be effectively internalized by tumor cells and endosomal escape to release DTX and ROR1 siRNA. In 4T1 tumor-bearing mice, BBRM could be targeting delivered to tumor and lung tissues, with good biosafety, achieving a tumor inhibition rate of 74.1% and inhibiting lung metastasis. By integrating chemotherapy and RNA interference therapy, BBRM successfully co-delivered chemotherapeutic agents and siRNA to improve the therapeutic efficacy of triple-negative breast cancer and provided a promising strategy for clinical transformation. STATEMENT OF SIGNIFICANCE: Chemotherapy is still the primary treatment for triple-negative breast cancer (TNBC) after surgery ablation, but it causes side effects without targeting capacity. ROR1 is significantly expressed in TNBC cells, and RNA interference for ROR1 can suppress ROR1 gene expression to inhibit tumor proliferation. However, as oligonucleotides, effect of ROR1 siRNA is limited by susceptibility to clearance and difficulty in endosomal escape. In this work, we designed a nanodevice based on a docetaxel (DTX) prodrug that targets ROR1 for the synergistic therapy of TNBC. We constructed a nanoparticle (BBRM) for co-delivery of the DTX and ROR1 siRNA. The BBRM could be effectively internalized by tumor cells and endosomal escape. The ROR1 siRNA downregulated ROR1 protein expression and improved the anti-proliferative and anti-metastatic effects. In addition, BBRM reversed the immunosuppressive tumor microenvironment, thus improving breast cancer therapeutic efficacy. It was a pioneering investigation in synergistic chemo-gene therapy by co-delivering DTX and ROR1 siRNA for TNBC treatment.

Keywords: ROR1 siRNA; docetaxel; pH responsive; prodrug nanoparticle; triple-negative breast cancer.