1. Academic Validation
  2. Simultaneous blockage of contextual TGF-β by cyto-pharmaceuticals to suppress breast cancer metastasis

Simultaneous blockage of contextual TGF-β by cyto-pharmaceuticals to suppress breast cancer metastasis

  • J Control Release. 2021 Aug 10;336:40-53. doi: 10.1016/j.jconrel.2021.06.012.
Yanyi Li 1 Qifan Hu 1 Weishuo Li 1 Shijing Liu 1 Kaiming Li 1 Xiaoyu Li 1 Junjie Du 1 Zexuan Yu 1 Cong Wang 2 Can Zhang 3
Affiliations

Affiliations

  • 1 State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, China Pharmaceutical University, Nanjing 210009, China.
  • 2 State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, China Pharmaceutical University, Nanjing 210009, China. Electronic address: wangcong@cpu.edu.cn.
  • 3 State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, China Pharmaceutical University, Nanjing 210009, China. Electronic address: zhangcan@cpu.edu.cn.
Abstract

It remains challenging to treat tumor metastasis currently in the LIGHT of multiple cascade processes of tumor metastasis. Additionally, multiple clinical drugs for metastasis have quite limited therapeutic potential and even facilitate metastasis in preclinical models. Thus, potential metastasis targets and novel metastasis-directed drugs are urgently needed to be further developed. Herein, Transforming Growth Factor-β (TGF-β) is verified to contribute to lung metastasis in a context-dependent manner in the 4T1 orthotopic tumor-bearing mice model, which induces epithelial-mesenchymal-transition (EMT) to promote tumor dissemination from the primary site and dampens the anti-tumor response of neutrophils to support tumor colonization at the metastatic niche. In view of neutrophils' superior tropism towards both inflammatory primary tumor and metastatic niche, SB525334, a TGF-β Receptor Inhibitor, is loaded into cationic Liposome (SBLP) which is subsequently incorporated into neutrophils to yield the cyto-pharmaceuticals (SBLP/NE). The systemically infused SBLP/NE can simultaneously migrate into both primary and metastatic sites, then release SB525334 in response to tumor stimuli, and contextually inhibit TGF-β-mediated-EMT and phenotype reversal of infiltrated neutrophils, showing substantial metastasis suppression efficacy without causing any detectable toxicities. This project shifts the paradigm for metastasis suppression therapy by simultaneous blockage of contextual TGF-β using metastatic-cascades-targeting neutrophil cyto-pharmaceuticals.

Keywords

Cyto-pharmaceuticals; Neutrophils; Simultaneous blockage; Targeting metastasis; Transforming growth factor-β.

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