Phase‐shifted pentafluorobutane nanoparticles for ultrasound imaging and ultrasound‐mediated hypoxia modulation

• Published in: Journal of cellular biochemistry Vol. 120; no. 10; pp. 16543 - 16552
• Main Authors: Chen, Wei‐Jian, Zhang, Hua, Zeng, Xue‐Yi, Chen, Long, Fang, Gui‐Ting, Cai, Huai‐Hong, Zhong, Xing
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.10.2019
• Subjects: Cell adhesion & migration; Cell migration; Glycolysis; Hypoxia; hypoxic microenvironment; Imaging; Lactic acid; Modulation; nanoagents; Nanoparticles; Oxygen; oxygen‐loading ability; phase transformation; Phase transitions; Polyethylene glycol; Polylactic acid; Secretion; Transition temperature; Transition temperatures; Ultrasonic imaging; Ultrasound; ultrasound imaging; Vapor phases; nanoagents; ultrasound imaging; hypoxic microenvironment; oxygen-loading ability; phase transformation
• ISSN: 0730-2312; 1097-4644
• DOI: 10.1002/jcb.28914

The integration of ultrasound (US) contrast enhancement with oxygen‐loading nanoagents provide the synergistic strategy for simultaneously US imaging and hypoxic microenvironment modulation. Herein, we synthesize pentafluorobutane (PFB)‐loading methoxy poly(ethylene glycol)‐b‐poly(l‐lactide) (PLLA) nanoparticle as the novel US‐contrast‐enhanced agent and demonstrate that PFB@PLLA effectively loads oxygen. We characterize the nanosize, phase‐transformation property and oxygen‐loading amount of PFB@PLLA and investigate the effectiveness of these nanoagents in US‐contrast‐enhanced imaging. The PFB@PLLA displays a perfect temperature‐responsive phase‐transition property and its liquid‐to‐gas phase transition temperature is 45°C, which produces microbubbles in the targeted regions. Moreover, PFB@PLLA loads high amount of oxygen and US‐triggering PFB@PLLA reoxygenation effectively inhibits the expression of hypoxia‐related proteins (HIF‐1α and CAIX), reduces lactate secretion and glycolysis, which modulates hypoxic microenvironment and inhibits cancer cell migration and invasion in vitro. This study demonstrates that the US contrast‐enhanced activity of PFB@PLLAs and the promising utility of oxygen‐loading nanoagents to improve hypoxic microenvironment. The integration of ultrasound contrast‐enhanced diagnostic imaging technique with reoxygen‐loading cancer therapy could allow the real‐time guidance, monitoring, and assessment of cancer therapeutic procedures and effects. Here we investigated the use of methoxy poly(ethylene glycol)‐b‐poly(l‐lactide) (mPEG‐PLLA) carrying liquid pentafluorobutane (PFB) (PFB@PLLAs) as a contrast agent for ultrasound imaging and aimed to increase the oxygen‐loading amount for hypoxia cancer microenvironment.