Department of Agricultural and Biological Engineering, Bindley Bioscience Center, Purdue Center for Cancer Research, Purdue University, 225 South University Street, West Lafayette, Indiana, 47907, USA.
Purdue University Center for Cancer Research, West Lafayette, Indiana, 47907, USA.
Sci Rep. 2017 Aug 24;7(1):9268. doi: 10.1038/s41598-017-08988-7.
Targeting the hypoxic tumor microenvironment has a broad impact in cancer epigenetics and therapeutics. Oxygen encapsulated nanosize carboxymethyl cellulosic nanobubbles were developed for mitigating the hypoxic regions of tumors to weaken the hypoxia-driven pathways and inhibit tumor growth. We show that 5-methylcytosine (5mC) hypomethylation in hypoxic regions of a tumor can be reverted to enhance cancer treatment by epigenetic regulation, using oxygen nanobubbles in the sub-100 nm size range, both, in vitro and in vivo. Oxygen nanobubbles were effective in significantly delaying tumor progression and improving survival rates in mice models. Further, significant hypermethylation was observed in promoter DNA region of BRCA1 due to oxygen nanobubble (ONB) treatment. The nanobubbles can also reprogram several hypoxia associated and tumor suppressor genes such as MAT2A and PDK-1, in addition to serving as an ultrasound contrast agent. Our approach to develop nanosized oxygen encapsulated bubbles as an ultrasound contrast agent for methylation reversal is expected to have a significant impact in epigenetic programming and to serve as an adjuvant to cancer treatment.
针对缺氧肿瘤微环境在癌症表观遗传学和治疗中有广泛的影响。我们开发了包载氧气的纳米级羧甲基纤维素纳米气泡，用于减轻肿瘤的缺氧区域，削弱缺氧驱动的通路并抑制肿瘤生长。我们表明，使用亚 100nm 尺寸范围的氧气纳米气泡，可以通过表观遗传调控使肿瘤缺氧区域的 5- 甲基胞嘧啶（5mC）去甲基化得到恢复，从而增强癌症治疗效果，在体外和体内实验中均得到证实。氧气纳米气泡在小鼠模型中能够显著延缓肿瘤进展并提高存活率。此外，由于氧纳米气泡（ONB）的治疗，BRCA1 启动子 DNA 区域观察到明显的高甲基化。纳米气泡还可以重新编程几种与缺氧相关的肿瘤抑制基因，如 MAT2A 和 PDK-1，此外还可以作为超声造影剂。我们的方法是开发纳米级氧气包封气泡作为超声造影剂用于甲基化逆转，有望在表观遗传学编程中产生重大影响，并作为癌症治疗的辅助手段。
