Jiangpei Shi,1,* Rongguang Zhang,1,* Yu Wang,1 Yingwei Sun,1 Xiaoyan Gu,1 Yu An,1 Xinyu Chai,1 Xiaoyu Wang,2 Zhi Wang,1 Yaqi Lyu,1 Teng Guo,1 Nianping Feng,1 Ying Liu1 

1School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, People’s Republic of China; 2Experiment Center for Science and Technology, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Nianping Feng; Ying Liu, Email npfeng@shutcm.edu.cn; debbyly@shutcm.edu.cn

Background: Metastasis is a complex process involving multiple factors and stages, in which tumor cells and the tumor microenvironment (TME) play significant roles. A combination of orally bioavailable therapeutic agents that target both tumor cells and TME is conducive to prevent or impede the progression of metastasis, especially when undetectable. However, sequentially overcoming intestinal barriers, ensuring biodistribution in tumors and metastatic tissues, and enhancing therapeutic effects required for efficient therapy remain challenging.
Methods: Inspired by the unique chemical features of natural herbs, we propose an oral herb–nanoparticle hybrid system (HNS) formed through the self-binding of Platycodon grandiflorum–Curcuma zedoaria (HG), a herb pair/group used in clinical practice to treat breast cancer metastasis, to lipid–polymer nanoparticles (LPNs) loaded with silibinin. The molecular structure responsible for HG association with LPNs was assessed using surface-enhanced Raman spectroscopy for HNS surface chemistry characterization. Moreover, the molecular class of HG was identified using UPLC–Orbitrap–MS/MS to further confirm the surface binding. Mucus diffusion and in vivo biodistribution were evaluated using in vitro multiple-particle tracking and environment-responsive fluorescence probe in 4T1 tumor-bearing mice, respectively. The alleviation of breast cancer metastasis was assessed in 4T1 tumor-bearing mice, and the underlying mechanism was investigated.
Results: The HNS reduced particle–mucus interactions by altering hydrophilicity and surface characteristics compared to LPNs. The epithelium transportation of HNS and absorption through Peyer’s patch in mice were improved, promoting their biodistribution in the lung and tumor tissues. Furthermore, the HNS alleviated lung metastasis by inducing cell apoptosis and regulating the expression of MMP-9 and TGF-β 1, which altered the TME in 4T1 tumor-bearing mice.
Conclusion: HNS provides an appealing system with multi-component binding of herbal medicine to facilitate both oral nanoparticle delivery efficiency and the alleviation of lung metastasis. This strategy may potentially help improve treatment for patients with breast cancer.

Keywords: herb–nanoparticle hybrid system, intestinal biological barrier, tumor microenvironment, breast cancer lung metastasis