Lenvatinib- and vadimezan-loaded synthetic high-density lipoprotein for combinational immunochemotherapy of metastatic triple-negative breast cancer

Chao Zheng; Wen Zhang; Jinming Wang; Yihui Zhai; Fengqin Xiong; Ying Cai; Xiang Gong; Binyu Zhu; Helen He Zhu; Hao Wang; Yaping Li; Pengcheng Zhang

doi:10.1016/j.apsb.2022.02.021

Lenvatinib- and vadimezan-loaded synthetic high-density lipoprotein for combinational immunochemotherapy of metastatic triple-negative breast cancer

Acta Pharm Sin B. 2022 Sep;12(9):3726-3738. doi: 10.1016/j.apsb.2022.02.021. Epub 2022 Feb 25.

Authors

Chao Zheng^{1

2}, Wen Zhang^{1

2}, Jinming Wang³, Yihui Zhai^{2

4}, Fengqin Xiong^{1

2}, Ying Cai^{2

4}, Xiang Gong^{1

2}, Binyu Zhu^{2

4}, Helen He Zhu³, Hao Wang¹, Yaping Li^{2

4

5}, Pengcheng Zhang^{2

6

4}

Affiliations

¹ China State Institute of Pharmaceutical Industry, Shanghai 201203, China.
² State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
³ State Key Laboratory of Oncogenes and Related Genes, Renji-Med-X Stem Cell Research Center, Department of Urology, Ren Ji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200135, China.
⁴ University of Chinese Academy of Sciences, Beijing 100049, China.
⁵ Bohai Rim Advanced Research Institute for Drug Discovery, Yantai 264000, China.
⁶ Yantai Key Laboratory of Nanomedicine & Advanced Preparations, Yantai Institute of Materia Medica, Yantai 264000, China.

Abstract

Metastatic triple-negative breast cancer (TNBC) is the most aggressive type of breast cancer. Combination of systemic chemotherapy and immune checkpoint blockade is effective but of limited benefit due to insufficient intratumoral infiltration of cytotoxic T lymphocytes (CTLs) and the accumulation of immunosuppressive cells. Herein, we designed a lenvatinib- and vadimezan-loaded synthetic high-density lipoprotein (LV-sHDL) for combinational immunochemotherapy of metastatic TNBC. The LV-sHDL targeted scavenger receptor class B type 1-overexpressing 4T1 cells in the tumor after intravenous injection. The multitargeted tyrosine kinase inhibitor (TKI) lenvatinib induced immunogenic cell death of the cancer cells, and the stimulator of interferon genes (STING) agonist vadimezan triggered local inflammation to facilitate dendritic cell maturation and antitumor macrophage differentiation, which synergistically improved the intratumoral infiltration of total and active CTLs by 33- and 13-fold, respectively. LV-sHDL inhibited the growth of orthotopic 4T1 tumors, reduced pulmonary metastasis, and prolonged the survival of animals. The efficacy could be further improved when LV-sHDL was used in combination with antibody against programmed cell death ligand 1. This study highlights the combination use of multitargeted TKI and STING agonist a promising treatment for metastatic TNBC.

Keywords: Combination therapy; High-density lipoprotein; Immune checkpoint blockade; Immunotherapy; Lenvatinib; Metastasis; Triple-negative breast cancer; Vadimezan.