Department of Biomedical Engineering, The Hong Kong Polytechnic University, Hung Hom, Hong Kong Special Administrative Region.
Department of Biomedical Engineering, The Hong Kong Polytechnic University, Hung Hom, Hong Kong Special Administrative Region.
Acta Biomater. 2020 May;108:313-325. doi: 10.1016/j.actbio.2020.03.034. Epub 2020 Apr 5.
Tumor hypoxia is believed to be a factor limiting successful outcomes of oxygen-consuming cancer therapy, thereby reducing patient survival. A key strategy to overcome tumor hypoxia is to increase the prevalence of oxygen at the tumor site. Oxygen-containing microbubbles/nanobubbles have been developed to supply oxygen and enhance the effects of therapies such as radiotherapy and photodynamic therapy. However, the application of these bubbles is constrained by their poor stability, requiring major workarounds to increase their half-lives. In this study, we explore the potential of biogenic gas vesicles (GVs) as a new kind of oxygen carrier to alleviate tumor hypoxia. GVs, which are naturally formed, gas-filled, protein-shelled compartments, were modified on the surface of their protein shells by a layer of liposome. A substantial improvement of oxygen concentration was observed in hypoxic solution, in hypoxic cells, as well as in subcutaneous tumors when lipid-GVs(O) were added/tail-injected. Significant enhancement of tumor cell apoptosis and necrosis was also observed during photodynamic therapy (PDT) in the presence of lipid-GVs(O) both in vitro and in vivo. Lipid-GVs(O) alone induced no obvious change in cell viability in vitro or any apparent pathological abnormalities after mice were tail-injected with them. In all, lipid-GVs exhibited promising performance for intravenous gas delivery, enhanced PDT efficacy and low toxicity, a quality that may be applied to alleviate hypoxia in cancers, as well as hypoxia-related clinical treatments. STATEMENT OF SIGNIFICANCE: The development of stable oxygen-filled micro/nanobubbles capable of delivering oxygen to tumor sites is a major hurdle to enhancing the efficacy of cancer therapy. Currently, micro/nanobubbles are limited by their instability when oxygen is encapsulated, creating a large pressure gradient and surface tension. To improve stability, we modified the surfaces of GVs, a biogenic stable nanoscale hollow structure, as a new class of oxygen carriers. Lipid-coated GVs were found to be stable in solution and effective O carriers. This will overcome the limitations of coalescence, short circulation time of synthetic bubbles during application. Our surface-modified GVs demonstrated low toxicity in vitro cell in vivo, while also being able to overcome hypoxia-associated therapy resistance when combined with photodynamic therapy.
肿瘤缺氧被认为是限制耗氧癌症治疗成功的一个因素，从而降低了患者的生存率。克服肿瘤缺氧的一个关键策略是增加肿瘤部位的氧气含量。含氧量的微泡/纳米泡已被开发出来，以提供氧气，并增强放射治疗和光动力疗法等治疗方法的效果。然而，这些气泡的应用受到其较差的稳定性的限制，需要进行重大的补救措施来增加它们的半衰期。在这项研究中，我们探索了生物气穴（GVs）作为一种新的氧气载体来缓解肿瘤缺氧的潜力。GVs 是天然形成的、充满气体的、蛋白壳包裹的隔室，其蛋白壳表面通过一层脂质体进行了修饰。当添加/尾巴注射脂质-GVs(O)时，在缺氧溶液、缺氧细胞以及皮下肿瘤中都观察到氧浓度的显著提高。在存在脂质-GVs(O)的情况下，体外和体内的光动力治疗（PDT）也观察到肿瘤细胞凋亡和坏死的显著增强。单独的脂质-GVs(O)在体外对细胞活力没有明显的变化，也没有明显的病理异常，在给小鼠尾巴注射后。总之，脂质-GVs 表现出了有希望的静脉内气体输送性能、增强的 PDT 疗效和低毒性，这种特性可能适用于缓解癌症中的缺氧以及与缺氧相关的临床治疗。
开发能够将氧气输送到肿瘤部位的稳定充氧微/纳米泡是增强癌症治疗效果的主要障碍。目前，微/纳米泡受到包裹氧气时的不稳定性的限制，产生了较大的压力梯度和表面张力。为了提高稳定性，我们对生物稳定的纳米级空心结构的天然 GVs 进行了表面修饰，作为一种新型的氧气载体。发现脂质包裹的 GVs 在溶液中稳定且是有效的 O 载体。这将克服在应用过程中，与合成气泡的聚结、短循环时间相关的限制。我们表面修饰的 GVs 在体外细胞和体内实验中表现出低毒性，同时当与光动力治疗结合时，也能够克服与缺氧相关的治疗耐药性。
