Doxorubicin loaded exosomes inhibit cancer-associated fibroblasts growth: in vitro and in vivo study

Abstract

Abstract Cancer-associated fibroblast cells (CAFs) play a key role in the breast cancer (BC) microenvironment that induces resistance to chemotherapy. Adipose mesenchymal stem cells (ADMSCs) derived exosomes were utilized to deliver the doxorubicin (Dox) to BC cell lines (MDA-MB-231, MCF-7) and CAFs in both mono and co-culture systems. Immunocytochemistry (ICC) for VIMENTIN and flow cytometry for the CD45, CD34, CD73, and CD90 markers were used to confirm the phenotypic characteristics of CAFs and MSC cells. Dox was loaded into ADMSCs-derived exosomes (Exo-Dox) through sonication and its loading wasa confirmed by transmission electron microscope (TEM). Compared to free Dox, Exo-Dox showed a higher efficiency in inducing apoptosis and inhibiting growth and migration in co-culture cells with CAFs (P < 0.05). The up-regulation of H19 and UCA1 lncRNAs, associated with chemoresistance, was confirmed using real-time PCR in CAF-derived breast cancer patients, CAF-derived exosomes, and exosome-derived patient serums. H19 and UCA1 expression levels were significantly down-regulated in MDA-MB-231, MCF-7, and co-cultures of MDA-MB-231 and MCF-7 cells with CAFs that received Exo-Dox treatment. In vivo results indicated that ADMSCs-derived exosomes (MSC-Exos) can accumulate at the tumor site. Exo-Dox suppressed cancer cell growth and significantly decreased tumor size compared to PBS (p < 0.01). The findings confirmed the growth inhibition effects of Exo-Dox n in CAFs, BC cells, and tumor-bearing mice.

Keywords

• Cancer-associated fibroblast cells
• Exosomes
• Doxorubicin
• Breast cancer
• Drug delivery