Langmuir. 2019 Aug 6;35(31):10166-10172. doi: 10.1021/acs.langmuir.8b03650. Epub 2019 Feb 12.
Tumor hypoxia is a significant factor leading to the resistance of tumors to treatment, especially for photodynamic therapy and radiotherapy where oxygen is needed to kill cancer cells. Oxygen delivery agents such as oxygen-saturated perfluorocarbon nanoemulsions and lipid oxygen microbubbles have been employed to supply oxygen to hypoxic tumors with ultrasound activation. Such oxygen delivery systems are still associated with several drawbacks, including premature oxygen release and the dependence of external stimuli. To address these limitations, we developed oxygen nanobubbles that were enclosed by the acetalated dextran polymer shells for spontaneous oxygeneration in response to a minor pH drop in the tumor microenvironment. The acetalated dextran polymer shell serves as a robust barrier against gas dissolution in the circulating blood to retain the majority of the oxygen payload, and its pH-responsive property enables an abrupt burst release of oxygen in the mild acidic tumor microenvironment. The acetalated dextran oxygen nanobubbles exhibited excellent stability and biocompatibility. In vitro and in vivo experiments were conducted to investigate the pH-responsive oxygen release. The external stimuli-free supply of oxygen by the acetalated dextran oxygen nanobubbles was evaluated on CNE2 tumor-bearing mice, and the intratumoral oxygen level increased by 6-fold after the administration of the oxygen nanobubbles, manifesting that our pH-responsive oxygen nanobubbles hold great potential as a potent oxygen delivery agent to overcome the hypoxia-induced resistance.
肿瘤缺氧是导致肿瘤对治疗产生抵抗的一个重要因素，特别是在需要氧气来杀死癌细胞的光动力疗法和放射疗法中。人们已经使用了诸如氧饱和全氟化碳纳米乳液和脂质氧微泡等氧输送剂，通过超声激活为缺氧肿瘤提供氧气。然而，这些氧输送系统仍然存在一些缺点，包括过早释放氧气和对外界刺激的依赖性。为了解决这些限制，我们开发了氧纳米气泡，它们被乙酰化葡聚糖聚合物壳包围，以响应肿瘤微环境中轻微的 pH 值下降自发产生氧气。乙酰化葡聚糖聚合物壳作为一种坚固的屏障，可以防止气体在循环血液中溶解，从而保留大部分氧气负载，并且其 pH 响应特性可以使氧气在温和的酸性肿瘤微环境中突然爆发释放。乙酰化葡聚糖氧纳米气泡表现出优异的稳定性和生物相容性。进行了体外和体内实验来研究 pH 响应性氧气释放。在 CNE2 荷瘤小鼠上评估了乙酰化葡聚糖氧纳米气泡的无外部刺激的氧气供应，并且在给予氧纳米气泡后，肿瘤内的氧气水平增加了 6 倍，表明我们的 pH 响应性氧纳米气泡作为一种有效的氧输送剂具有很大的潜力，可以克服缺氧诱导的抵抗。
