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Locally-active oxygen-producing Cyanobacteria as adjuvant therapy for late-stage solid tumors

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jnikola May 31, 2021
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The idea is to flood tumors with oxygen produced by cyanobacteria and at the same time use ROS-producing chemotherapeutics like platinum-based drugs.

The Introduction

This session was inspired by the fact that a low oxygen environment is often related to the more resistant and aggressive tumor types. How?
The abnormalities in the tumor cells and tissues often lead to lower oxygenation of the tumor environment. Coupled with high metabolism and proliferation, this leads to hypoxia (disrupted oxygen balance - low influx and high demand for oxygen). It is believed that hypoxia promotes more resistant and aberrantly proliferating tumorigenic phenotypes due to the struggle to survive (lack of energy due to glycolisis), increased angiogenesis and spread (metastasis) .

Up-to-Date Oxygen Therapies

  • Whole body oxygen flood by ozone or hyperbaric oxygen therapy - there are no clear evidence of the general safety (the harm for the whole body) and efficiency.
  • Local oxyigen flood - oxygen delivery systems like oxygen nanoshuttles ; not proven efficient

The concept

The first thing would be to diagnose and determine the type of cancer in patients. Patients with solid tumors stage 3 and 4 (tumor spread) would be chosen for this co-treatment. Besides the regular therapy (platinum-based or similar chemotherapy), patients would get a dose of cyanobacteria and nanoparticles dissolved in saline, locally administered at the tumor site. The tumor would then be locally irradiated by near-infrared light to start up the cyanobacteria oxygen production.
If the lack of oxygen potentiates mutagenic growth, angiogenesis and spread, this way we should keep it local and less agressive and consequently, more responsive to the first line therapy. The main advantage compared to the other local one-time oxygen therapies would be the prolonged local oxygen production due to the photosynthesis of cyanobacteria.

The questions

What type of cancer would benefit the most from oxygen therapy?
In what stage would local oxygen therapy be the most effective?
What parameters should we use to measure the effect of this therapy?







Creative contributions

A lot of complications

Povilas S
Povilas S May 31, 2021
It seems to me that the idea would be very complicated to realize in practice. First - cyanobacteria don't naturally live inside other organisms, therefore it's highly unlikely that they would survive inside the physiological medium of the human body. Being photosynthetic they need direct light for their survival. Even though they can tolerate low levels of light, like at the bottom of the water body, near-infrared light won't do it, because it can't effectively penetrate tissues, it will be converted into heat at the surface of the body. Even if some of it will penetrate deeper in the form of electromagnetic radiation, I'm guessing this would be far from enough of what's required to cause and maintain photosynthesis.

But even if you managed to somehow "light them up" inside the body, I doubt they would survive there in the first place, because of the physiological medium totally unfavorable for them - the specific salinity, the pH, the ferments, and other bioactive chemicals that can potentially damage them, not to mention they need sufficient amounts of CO2 for photosynthesis. Just delivering localized oxygen to the tumor area sounds much much easier.
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jnikola3 years ago
Thank you Povilas S for raising these questions. I will try to answer all of them.
It's undoubtedly a very complicated idea with many weak spots and that is why it's posted here - so you can help me overcome these!

The main reason why I thought about this at the beginning is the poor efficiency of localized oxygen delivery therapies. My aunt has a private clinic where she tries to fight cancer with both medical and alternative methods, including hyperbaric oxygen therapy. All of the current oxygen therapies were unfortunately shown to be immunostimulatory from time to time, but not resulting in any statistically relevant benefit to the tumor treatment itself.

I was expecting the main concern of readers to be the effect of cyanobacteria being present inside all the blood vessels, heart, tissues, brain and the effects they would cause. But, as I realized, your main concern is the survival of cyanobacteria inside the human blood.

In 2018, researchers found cyanobacteria living 600 meters deep in the air pockets of rocks [1]. They concluded that they used hydrogen as an electron donor and somehow still produced enough energy to survive. Although it is here to support my theory, I would love to see how these cyanobacteria performed photosynthesis when exposed to the sunlight again because it was not the same type of cyano as mentioned in my contribution [2].
In the same contribution, I cited an article where researchers injected cyanobacteria inside a mice's brain. It was also done in rats in another research and it was shown that no immune response was activated, no significant aberrations in specific blood cell counts were reported and rats' hearts showed better fitness even a month after.

Now let's focus on specific problems of salinity, pH, and other chemicals in blood and their effects on cyanobacteria. Although there is no discussion that cyanobacteria are really tough, it is worthy to mention that the pH of blood is around 7.4, just around the center of the optimal pH spectrum of the CCM protein (protein necessary for fixation of CO2 in all photosynthetic organisms) [3]. That's why I think they would have no salinity or pH problems, but it's definitely something that should be discussed and optimized. The same thing is with blood toxins - since they are single-cell algae, I think anything that would harm them would, no doubt, harm human cells, too.

So the idea is that cyanobacteria would circulate the blood for some time. As the CO2 and O2 ratio in the photosynthetic reaction is balanced (6 CO2 + 6 H2O → C6H12O6 + 6 O2), they would, in my opinion, function like small dispersed lungs and raise the efficiency of respiration.

The main problem is the generation of electrons needed for the reaction while the light is low. The near-infrared light was shown to pass deep up to 1 cm in the tissue (for now) and cyanos in the mice brain tissue produced oxygen via light emitted from nanoparticles. The key thing would be to fine-tune the sensitivity of the nanoparticles to emit as much light as possible with almost no near-infrared signal. The next thing would be to engineer cyanos to produce maximum oxygen in light and a small portion in the dark conditions (probably based on hydrogen electron donor as described in example with cyanos in rocks). The engineering problem should not be hard if we consider the fact that one cyanobacterium called Synechocystis sp. was the third organism that had its genome sequenced, the genetic engineers should have no trouble engineering "the perfect" cyanobacteria for this purpose (as shown here [4]).

Did I at least partially answered some of your questions?

PS Another thing is that we should be careful on sugar levels after the cyanos do their work.

1 https://www.pnas.org/content/115/42/10702
2 https://pubs.acs.org/doi/10.1021/acs.nanolett.1c00719
3 https://www.pnas.org/content/113/36/E5354
4 https://www.pnas.org/content/118/11/e2021523118
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Shubhankar Kulkarni
Shubhankar Kulkarni3 years ago
Juran You have done a great deal of research on the idea!

All you points seems convincing. However, I can't wrap my head around the observation that the injected cyanobacteria did not elicit an immune response in the rodents. By simple logic, cyanobacteria are foreign particles and they definitely have antigens. What makes the body treat them as self? Is it something that the cyanobacteria do to avoid being detected? In that case, they can be more dangerous to us than we are to them. As an example, a single or a few mutations in them may make them pathogenic without being detected by the body's immune system and that can be lethal.

However, we have the option of installing a kill-switch in them during genetic engineering.
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jnikola3 years ago
Shubhankar Kulkarni That's also my biggest concern. I am currently debating with my fellow algae expert about how dangerous could it be and what are the weak points of the idea. His first comment was "oh, good, we have cyanobacteria and they are not pathogenic". That was the thought that got me like "mmm, okay, it could work". Based on what he told me, I am sure cyanobacteria get eliminated by the host immune system, the same way as other bacteria. It's just a matter of their effect and half-life, I guess. But definitely, a thing that needs to be carefully worked out.
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