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Metricsdetails 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.

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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 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. The nanobubbles can also reprogram several 42 nu poate slăbi associated and tumor suppressor genes such as MAT2A and PDK-1, in addition to serving as an ultrasound contrast agent.

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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.

Introduction Epigenetics plays an important role in regulating the expression of genes and corresponding cellular and molecular pathways1. DNA methylation i. Addition of methyl groups to the cytosine derivatives in the DNA sequence can render the associated genes transcriptionally inactive5.

DNA demethylation can lead to a hypomethylated state, but is counteracted by active DNA methylation to achieve a balanced methylation level6, 7. In neoplasia, the unregulated proliferation of cellular mass, without a sustainable rate of angiogenesis, leads to the development of hypoxic conditions inside the tumor8.

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In response to the pervasive hypoxic environment, several oncogenic processes occur in the cells, one of which is epigenetic alterations, resulting in an increase in tumor growth and survival of cancer cells9, These alterations include global hypomethylation primarily of oncogenes rendering them active ideal pierdere în greutate burlington ma, gene-specific hypermethylation of CpG ideal pierdere în greutate burlington ma in the promoter regions of tumor suppressor genes, rendering them inactiveand inducing cell proliferation via dysregulated cell growth3.

Although epigenetic therapy in the laboratory and clinics have largely focused on changes at gene promoters15, 16, epigenetic abnormalities such as DNA 5mC methylation across the genome17 are now being looked upon as diagnostic tumor staging, outcome prediction, and malignancy and therapeutic targets epigenetic drugs.

Regulation of the hypoxic microenvironment and epigenetic events are promising steps in anticancer therapies because several hypoxia18,19,20 and epigenetic15, 21,22,23 targeted therapies have shown efficacy in the clinic24,25, Further, this view is also supported by findings on the effect of supplemental oxygen that weaken the hypoxia-driven pathways to improve cancer immunotherapy to promote tumor regression Supplemental respiratory oxygen has shown significant lung tumor regression and long-term survival in mice and is being proposed as a treatment option27,28,29 by combining it with existing cancer immunotherapies.

However, the toxicity and nonspecific inflammatory response30, 31 in addition to its large instrumentation footprint, diminishes its potential as a viable therapeutic option.

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Hence the motivation to develop injectable and safer treatment options that weaken the hypoxia-driven global hypomethylation and hypoxia-adaptive pathways. Herein, we reason that delivery of nanosize oxygen bubbles specifically 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. Global 5mC methylation along with HIF-1α levels were monitored in vitro and in vivo during the course of tumor regression upon hypoxia reversal, using human cervical cancer HeLa and murine bladder cancer MB49 tumor models.

Further, promoter methylation analysis was used to assess a group of tumor suppressor genes.

Our results indicate that the oxygen nanobubbles can potently alter the epigenetic state of the cell cycle-related genes and mitigate cancer cell proliferation. Our approach provides an injectable, nano-scale oxygen delivery platform to mitigate hypoxia and to alter the epigenetic state, thus providing an opportunity for epigenetic therapy approaches by destabilizing the hypoxia-adaptive pathways in the tumor.

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Results e hypothesize that alteration of DNA hypomethylation in hypoxic cancer cells can be achieved by the delivery of oxygen to the cellular microenvironment with nanosize oxygen bubbles Fig. In particular, our approach consists of encapsulating oxygen ideal pierdere în greutate burlington ma a sodium carboxymethylcellulose polymeric shell Fig. High resolution TEM micrographs show that the synthesized nanobubbles have a spherical shape Fig.

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Dynamic light scattering DLS shows that the size distribution of nanobubbles is in the range between 50— nm with a normal distribution centered around 70 nm Fig. Further, sodium carboxymethylcellulose is a commercially used, FDA-approved pharmaceutical excipient.

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Upon uptake, the acidic microenvironment around and inside the tumor cells34 will cause the nanobubble shells to disintegrate, thereby increasing the cellular oxygen levels.

We expect the release of oxygen inside the hypoxic cells will destabilize the hypoxia-adaptive pathways and reprogram the cellular epigenome to attain normal DNA methylation levels, or cause global hypermethylation.

The targeted oxygen delivery is also expected to promote the regression of tumor growth in the hypoxic xenografted MB49 bladder cancer and HeLa cervical cancer tumors. Figure 1 Oxygen Nanobubble configuration and mechanism of 5mC hypermethylation.

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Significantly enhanced dark field microscopy images are provided. Full size image Figure 2 In vitro characterization, hypoxia reprogramming, and imaging of nanobubbles.

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The contrast generated is due to oxygen trapped inside nanobubbles. The results are mean values from three independent experiments.

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Error bars represent ± s. Note that there is a significant linear relationship between mean ultrasound gray scale intensity and concentration of nanobubbles see Supplementary Fig. Full size image In addition to reoxygenation, we anticipate that oxygen nanobubbles will act as contrast agents for ultrasound imaging.

Nanobubbles also possess unique light scattering and absorption characteristics as demonstrated using dark field microscopy Fig.

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To test the ultrasound imaging intensity response to increasing concentration of nanobubbles, agarose gel molds were prepared with varying concentration of nanobubbles Supplementary Fig. B-mode ultrasound images of injected nanobubbles are shown in Fig. A linear increase in ultrasound grey scale imaging intensity Fig.

Further, HeLa cell cultures grown in tissue culture plates were incubated either with oxygen nanobubbles or phosphate buffer saline PBS.

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After incubation for 24 h, the cell cultures were imaged using a element 22—55 MHz ultrasound transducer with a center frequency of 40 MHz for sample preparation and imaging details, see Methods Section. Images show that the spherical nanobubbles are suspended in the media as well as around the HeLa cells adhered to the bottom of the plate Supplementary Fig. The ultrasound gray scale imaging intensity in cell cultures with nanobubbles was significantly higher than the control without the addition of nanobubbles Supplementary Fig.

The proposed design allows for customization of its size to accommodate various oxygen carrying capacity capable of generating different ultrasound contrast intensity.

The 5mC levels in the hypoxic regions have been shown to rapidly decrease, independent of the cell proliferation cycle In our experiments, DNA was extracted after 48 h of incubation following a factorial experiment design data not shown to ensure sufficient time for the methylation changes to take effect Colorimetric enzyme-linked immunosorbent assay ELISA was used to quantify 5mC levels36 after the exposure of nanobubbles to a hypoxic environment Fig.

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Further, irrespective of the time of dose start of treatment at 0 h or 24 hno significant difference was observed in the methylation levels Fig. However, in cells treated with ideal pierdere în greutate burlington ma, i. A significant difference was observed Fig.

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Our observations infer that active 5mC levels in hypoxic tumor cells can be increased using oxygen nanobubbles in a dose-dependent manner, in vitro. Figure 3 ONBs perturb 5mC hypomethylation in vitro. The nanobubble treatment volume and time of treatment was the same for all samples.

The results are mean values from three independent experiments ± s.