期刊
JOURNAL OF CONTROLLED RELEASE
卷 352, 期 -, 页码 747-758出版社
ELSEVIER
DOI: 10.1016/j.jconrel.2022.11.006
关键词
Tumor acidity modulation; Endothelial-to-mesenchymal transition; Chemotherapy sensitization; Metastasis inhibition; Tumor microenvironment
资金
- National Natural Science Foundation for Distinguished Young Scholars [81625023]
- Na- tional Natural Science Foundation of China [82104103]
This study developed a combination strategy to enhance chemotherapy sensitivity and suppress tumor metastasis by modulating tumor microenvironment pH. It demonstrated significant inhibition of tumor growth and reduction of metastasis in an orthotopic breast cancer mouse model.
The abnormal metabolism of rapidly growing tumors can create an acidic tumor microenvironment (TME) that renders cancer cells resistant to chemotherapy and further facilitates endothelial-to-mesenchymal transition (EMT) progress to promote metastasis. Here, we developed a combination strategy consisting of (1) peri-tumorally injected scaffold that alleviates TME acidosis, and (2) intravenously injected nanoparticles that de-livers anti-cancer agents to tumor. Concurrent treatment with these two drug delivery systems profoundly delayed the growth of primary tumor and reduced the spontaneous metastasis to lung in an orthotopic breast cancer mouse model. Mechanism studies both in vitro and in vivo further revealed that neutralization of TME pH by the hydrogel scaffold sensitized cancer cells to nanoparticle-based chemotherapy, thereby strengthening the cytotoxicity against tumor growth; In parallel, reversal of tumor acidity downregulated various pro-metastatic proteins intratumorally to block the EMT progress, thereby reducing the metastatic potential of cancer cells. This work provided proof-of-concept demonstration that chemotherapy sensitization and EMT suppression could be synchronized by the modulation of TME pH, which may be potentially beneficial for simultaneous inhibition of tumor growth and cancer metastasis.
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