PDGFR-targeted nanovesicles for restraining breast cancer hepatic metastasis via hepatic stellate cell regression and NK cell activation

Abstract

Preventing breast cancer liver metastasis presents formidable challenges with multifaceted obstacles. In the case of acute and chronic liver injury, the disrupted liver microenvironment induced by activated hepatic stellate cells (aHSCs) would suppress immune surveillance and license the re-multiplication of disseminated tumor cells (DTCs). Herein, a cyclic peptide pPB modified nanovesicle with aHSCs targeting capability was constructed as CP-SB-siRNA to co-deliver hydrophobic SB431542 and nucleic acid drug CXCL12 siRNA. Due to the TGF-β signaling inhibition of SB431542, CP-SB-siRNA significantly suppressed the expression levels of genes coding the uppermost fibrosis-associated proteins including α-sma, Col-1 and Col-3 in aHSCs. On the other hand, the gene and protein expression level of metastasis-associated chemokine CXCL12 was significantly decreased. In addition, CP-SB-siRNA could regain the function of NK cells and attenuate the breast cancer proliferation through CXCL12-CXCR4 axis. On both breast cancer spontaneous metastasis with fibrosis mouse model and breast cancer via hematogenous metastasis with fibrosis mouse model, CP-SB-siRNA successfully reversed hepatic fibrosis by regressing aHSCs, and thereby restored the liver microenvironment, ultimately inhibiting breast cancer hepatic metastasis. This nanomaterial vector, featuring targeting and drug co-delivery functionalities, exhibited a great potential to restrain breast cancer hepatic metastasis based on the relationship among aHSCs, NK cells and DTCs.