Abstract
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.
Highlights
Epigenetics plays an important role in regulating the expression of genes and corresponding cellular and molecular pathways[1]
We reason that delivery of nanosize oxygen bubbles to hypoxic regions would help to regulate the epigenetic state by destabilizing the hypoxia-mediated pathways such as hypoxia inducible factor (HIF)[32] that promote tumor progression
Dynamic light scattering (DLS) shows that the size distribution of nanobubbles is in the range between 50–200 nm with a normal distribution centered around 70 nm (Fig. 2b)
Summary
Epigenetics plays an important role in regulating the expression of genes and corresponding cellular and molecular pathways[1]. The ultrasound gray scale imaging intensity in cell cultures with nanobubbles was significantly higher than the control without the addition of nanobubbles (Supplementary Fig. 4). In cells treated with nanobubbles, i.e. addition of nanobubbles (0.5 mg/mL) at 0 h and after 24 h of incubation, a rapid and significant increase in 5mC DNA methylation levels was observed.
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