Ultrasound Triggered Tumor Oxygenation with Oxygen-Shuttle Nanoperfluorocarbon to Overcome Hypoxia-Associated Resistance in Cancer Therapies

TLDR

Tumor hypoxia limits the effectiveness of therapies such as photodynamic therapy and radiotherapy that require oxygen for cancer cell destruction. The study aims to develop an ultrasound‑triggered, nano‑perfluorocarbon oxygen shuttle that can modulate tumor hypoxia and be applied across different tumor models. Albumin‑stabilized PFC nanodroplets are injected intravenously under hyperoxic breathing, and low‑power ultrasound applied to the tumor releases their lung‑adsorbed oxygen, after which the droplets return to the lung for reoxygenation. Repeated ultrasound‑induced oxygen release cycles markedly increased tumor oxygenation and improved photodynamic and radiotherapy outcomes, demonstrating a simple, clinically available strategy to overcome hypoxia‑associated resistance.

Abstract

Tumor hypoxia is known to be one of critical reasons that limit the efficacy of cancer therapies, particularly photodynamic therapy (PDT) and radiotherapy (RT) in which oxygen is needed in the process of cancer cell destruction. Herein, taking advantages of the great biocompatibility and high oxygen dissolving ability of perfluorocarbon (PFC), we develop an innovative strategy to modulate the tumor hypoxic microenvironment using nano-PFC as an oxygen shuttle for ultrasound triggered tumor-specific delivery of oxygen. In our experiment, nanodroplets of PFC stabilized by albumin are intravenously injected into tumor-bearing mice under hyperoxic breathing. With a low-power clinically adapted ultrasound transducer applied on their tumor, PFC nanodroplets that adsorb oxygen in the lung would rapidly release oxygen in the tumor under ultrasound stimulation, and then circulate back into the lung for reoxygenation. Such repeated cycles would result in dramatically enhanced tumor oxygenation and thus remarkably improved therapeutic outcomes in both PDT and RT treatment of tumors. Importantly, our strategy may be applied for different types of tumor models. Hence, this work presents a simple strategy to promote tumor oxygenation with great efficiency using agents and instruments readily available in the clinic, so as to overcome the hypoxia-associated resistance in cancer treatment.