Sensitization of Hypoxic Tumors to Radiation Therapy Using Ultrasound-Sensitive Oxygen Microbubbles.
Sensitization of Hypoxic Tumors to Radiation Therapy Using Ultrasound-Sensitive Oxygen Microbubbles.
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DOI：
10.1016/j.ijrobp.2018.01.042
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发表时间：
2018-05-01
期刊：
影响因子：
--
通讯作者：
Wheatley MA
中科院分区：
文献类型：
--
作者：
Eisenbrey JR;Shraim R;Liu JB;Li J;Stanczak M;Oeffinger B;Leeper DB;Keith SW;Jablonowski LJ;Forsberg F;O'Kane P;Wheatley MA
实体瘤的大部分体积通常存在于长期缺氧的微环境中，这种微环境已被证明会导致化疗和放射治疗的抵抗。在治疗前全身输氧已被证明在逆转这种抵抗方面很大程度上无效。表面活性物质包裹的氧气微泡可以静脉注射，并在非侵入性超声触发时用于局部升高肿瘤的氧气水平，已有报道。在这项工作中，我们证明了这些药物在小鼠模型中成功并持续地将乳腺肿瘤的氧合水平提高了20毫米汞，显著高于对照组注射生理盐水或未触发的氧气微泡(p<；0.001)。利用光声成像，我们还表明氧气输送不依赖于血红蛋白输送，从而使氧气输送到肿瘤的无血管区域。最后，我们表明，在放射治疗前立即用这种方法克服低氧几乎是放射敏感性的三倍。这种放射敏感性的改善导致了大约30天的肿瘤控制改善，在肿瘤生长和动物存活方面提供了统计上的显著改善(p<；0.03)。这项研究的结果证明了超声触发的氧气输送到实体肿瘤的潜在优势，并证明了未来将微泡平台转化为临床的努力。
Much of the volume of solid tumors typically exists in a chronically hypoxic microenvironment which has been shown to result in both chemo- and radiotherapy resistance. Systemic delivery of oxygen prior to therapy has proven largely ineffective in reversing this resistance. Surfactant-shelled oxygen microbubbles that can be injected intravenously and used to locally elevate tumor oxygen levels when triggered by noninvasive ultrasound have been previously reported. In this work, we show that these agents successfully and consistently increase breast tumor oxygenation levels in a murine model by 20 mmHg, significantly more than control injections of saline or untriggered oxygen microbubbles (p < 0.001). Using photoacoustic imaging, we also show that oxygen delivery is independent of hemoglobin transport, enabling oxygen delivery to avascular regions of the tumor. Finally, we show that overcoming hypoxia by this method immediately prior to radiation therapy nearly triples radiosensitivity. This improvement in radiosensitivity results in roughly 30 days of improved tumor control, providing statistically significant improvements in tumor growth and animal survival (p < 0.03). Findings from this study demonstrate the potential advantages of ultrasound-triggered oxygen delivery to solid tumors and warrant future efforts into clinical translation of the microbubble platform.
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