Hyperbaric oxygen regulates tumor microenvironment and boosts commercialized nanomedicine delivery for potent eradication of cancer stem-like cells

Abstract

Cancer stem-like cells (CSCs) depend highly on hypoxia in solid tumors and represent an intractable challenge for marketed nanomedicines. Herein, we for the first time leveraged hyperbaric oxygen (HBO) therapy to help commercialized nanomedicines, including Doxil and Abraxane, eliminate CSCs in stroma-rich solid tumors, e.g., triple negative breast cancer (TNBC) and pancreatic ductal adenocarcinoma (PDAC), for efficient cancer therapy. Mechanistically, we revealed that HBO disrupted hypoxia in solid tumors, thereby directly suppressing CSCs and cancer metastasis. More importantly, we found that HBO depleted excessive extracellular matrix, such as collagen and fibronectin, and thus normalized tumor blood vessels both structurally and functionally. As a consequence, HBO augmented the delivery of commercialized nanomedicines, but not small molecule drug, into solid tumors, in terms of tumor accumulation, deep penetration and cellular internalization, leading to efficient CSCs eradication and tumor inhibition. These results demonstrate that HBO enables commercialized nanomedicines to eliminate CSCs in stroma-rich solid tumors and suggest that the combination of HBO with commercialized nanomedicines is promising for the treatment of hypoxic solid tumors in the clinics.