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(@johan)
Joined: 2 years ago
Posts: 505
24/07/2020 10:11 pm  

@daniel

Why would I change because of the supp company, I reacted to @jcancom's recommendations of a private clinic to a recently diagnosed cancer patient, that's what started this change in mood. For me it was an eye-opener, that's it.

So basically, @jcancom can scream all day long "wow, everything's metabolic!" and when I say "maybe not everything, I get attacked. If that's not bias, ok.

No need to discuss this any further.

Again, I wish you all and everyone here all the best.


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Daniel
(@daniel)
Admin
Joined: 5 years ago
Posts: 844
24/07/2020 10:28 pm  
Posted by: @johan

@daniel

Why would I change because of the supp company, I reacted to @jcancom's recommendations of a private clinic to a recently diagnosed cancer patient, that's what started this change in mood. For me it was an eye-opener, that's it.

So basically, @jcancom can scream all day long "wow, everything's metabolic!" and when I say "maybe not everything, I get attacked. If that's not bias, ok.

No need to discuss this any further.

Again, I wish you all and everyone here all the best.

It's not true Johan. I reacted to your point not because being against J. You are welcome to have any arguments against anything as long as they are constructive. I reacted to your major change of position reflect in more than that reaction to J's comment. We don't need to discuss this again.

Anyway, I was thinking earlier about this event and realising that is impressive how people with similar and good intentions can end up having opposite discussion just because of a change in perception.

This is an important learning point for me and I will make sure in the future I will always check and be even more open to change my perceptions about others.

I believe you are a good person and hope you are willing to reconsider your perception.

Text never helps and often escalates things that in real life would never escalate. Like I said before, it's always my pleasure to make time and speak on the phone, video call, discuss and clarify things. I am sure this would help. I can even make time for that now. Just let me know when you like.

Kind regards,
Daniel


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Jcancom
(@jcancom)
Joined: 3 years ago
Posts: 434
25/07/2020 1:25 am  

Thank you everyone for a great discussion on lactate and syromet; it has exposed several interesting aspects of the lactate response for me. For example, as D noted metformin can create a systemic lactate increase which can obscure the tumor response. Yet, a well formulated treatment would offer the opportunity to more specifically monitor how cancer cells responded to treatment.

I think it is important to try and develop a clinical awareness of how the treatment is affecting the cancer. The lactate monitor offers potential to do this. Perhaps treat with syrosingopine monotherapy and metformin monotherapy at different doses to try and develop insight. The idea is to try and heighten  observational skill instead of only treating blindly.

GgE, I appreciate your specific questions about how we might interpret the lactate response. The intention of my initiating post was that we could explore this landscape in order to see what idea treasure might be discovered. What is especially interesting with science is that almost invariably what you find is not what you were expecting. It is humbling to be wrong so often, though it also offers a great opportunity to develop deeper understanding.

   


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Jcancom
(@jcancom)
Joined: 3 years ago
Posts: 434
25/07/2020 1:59 am  

johan, it is true; I have become even more excited about metabolics lately. Every once and a while on the compass and on the forum we have been able to find insights that actually help our friends. It requires a great deal of sifting and usually quite a bit of time, though with effort our sifting does seem to be productive. It is through collective effort that this is possible. My observation is that trying to attempt this alone is rarely successful. Leveraging a united purpose is in the best interests of all.   

I am beginning to have a good feeling about formulations. Formulations can typically greatly enhance cancer treatment at least in the sense of reducing effective doses by upwards of 1,000 fold. If those on forum could access and implement such technology (e.g., liposomes, chitosan, etc.), then we could witness a very large step forward in our treatment efforts.

The result that I recently posted to the vitamin C blog was especially impressive to me. As we know, vitamin C dosing has reached mega doses sometime in excess of 100 GRAMS daily. Yet, even this level of dosing often has only marginal clinical effects. With vitamin C nanoparticles, mice were treated at 200 mg/kg daily and this stopped tumor progression over ~ 1 month. This is on the treatment frontier and there could be dangers that are not obvious to us, though nanoparticles could be another step forward for us. What is especially encouraging is that directly targeting metabolics to cancer cells (ironically using the one nearly constant metabolic feature of cancer cell behavior lactate export --> low extracellular pH --> nanoparticle release signal) might allow us to avoid toxic chemicals altogether. Even ~~250 mg of nanoparticle vitamin C in humans might have such large anti-cancer effects as in the mice? This would be a new treatment era.

While you are correct that my metabolic enthusiasm might be somewhat naive and misplaced, admittedly there are other aspects to cancer, with our evolving understanding of treatment options other conceptions of cancer simply might not be necessary for effective therapy. One might rightfully wonder if properly  formulated vitamin C can be so effective, then how many other metabolic treatments might truly be needed for comprehensive cancer management?

I enjoy your posts and I am glad and strongly support your advocacy for the best interests readers of the blog. After all of these years our mission remains the same: To the best of our ability help those confronting cancer by researching the literature and suggesting potential treatment ideas to them. 

Best Wishes, J

         


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Daniel
(@daniel)
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25/07/2020 2:01 am  

@jcancom

Posted by: @jcancom

What is especially interesting with science is that almost invariably what you find is not what you were expecting. It is humbling to be wrong so often, though it also offers a great opportunity to develop deeper understanding.

J, this is so true. It happened to me several times while doing my experiments to see how everything connects pointing towards a (nice) conclusion, only to go the next day into the lab and obtain data indicating that the conclusion was wrong. That made me understand how important is to keep our mind open for new data, ready to change our deepest believes if strong arguments present, in order to be able to advance our understanding. Also, my most important discovery, that broke through two laws/barriers of physics of magnetism and optics, came from what initially looked like noise which most of the scientist would not even look at it. This is why I totally agree: the valuable answers come from unexpected directions and sources.


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Daniel
(@daniel)
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25/07/2020 2:03 am  

@jcancom

Posted by: @jcancom

suggesting potential treatment ideas to them. 

presenting potential treatment ideas.


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Jcancom
(@jcancom)
Joined: 3 years ago
Posts: 434
25/07/2020 2:22 am  

This is the central metabolic pathway of cancer that we have referred to endlessly through the years. Those who might casually dismiss the pathway's importance would need to reconcile the fact that inhibiting almost any enzyme in the chain can have large anti-cancer effects. It is enormously disappointing that no FDA approved drug appears to target any of the metabolic features that we discuss here so often. 

What is somewhat unique with syrosingopine is that it is the first treatment that can potentially block enolase. While gamma-enolase might be potentially an escape route, it does highlight a substantial weakness in cancer's logic: in a linear pathway of 10 steps, obstructing any one of the steps along the way can lead to a shutdown. Of particular interest with enolase obstruction is that even though it is the next to last step, it result in 0 net glycolysis generation: -2 + (2*1) ATP =0 ATP. Cancer cannot survive with 0 energy production.   


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(@johan)
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25/07/2020 2:32 am  
Posted by: @jcancom

with our evolving understanding of treatment options other conceptions of cancer simply might not be necessary for effective therapy. One might rightfully wonder if properly  formulated vitamin C can be so effective, then how many other metabolic treatments might truly be needed for comprehensive cancer management?         

Well J, if you're that convinced maybe you should try what Dr Barry Marshall did for peptic ulcers. 


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GgE
 GgE
(@gge)
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Posts: 222
25/07/2020 6:52 am  
Posted by: @johan

I recently started noticing the HUGE bias on this website, and there's clearly a reason why this is happening. 

I wish you guys good luck.

Johan, I like very much all that you have added to this forum for a long time.

I am not an expert in this field but I have noticed that even big pharma is recently recognizing the necessity and convenience of counting on cancer’s metabolic properties to design drugs that have a significant effect on cancer treatment.

Take for example alpelisib. It is the latest and most effective weapon available for hormone-sensitive cancers that have PIK3CA mutations and have progressed on endocrine and CDK inhibitor therapies.

Alpelisib is a targeted therapy agent which ostensibly aims at disabling the cancer cells proliferation signaling that goes through the PI3k/mTOR/AKT axis. It is highly successful in some patients but not in others. The difference? Glucose metabolism. Patients whose diets included high carb contents or could not sufficiently manage their blood glucose levels did not respond or stopped responding sooner than the rest. Diabetic and pre-diabetic patients who could not keep their blood glucose from getting too high (a notorious side effect of alpelisib) usually have to stop the treatment because it fails to them. Their cancer cells get daily insulin boosts that override alpelisib’s effects and continue to proliferate. I may be wrong but this effect came as a surprise to some of the researchers.

My impression is that there might be 2 kinds of anti-cancer drugs: Those that are known to have a metabolic effect as part of their effectiveness and those we don’t know yet, but we may one day find out

The bottom line if my long winding post is that nobody really knows everything any drug does and we all need to learn from every interested person, whether we accept their point of view or not, because they might turn out to be right.

Because of this and because of the legacy of brilliant ideas you have given us, I ask you to stay with us and overlook our differences. We can benefit from your help in fighting the common enemy, which is the universal ignorance about cancer.


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John Pizzuto
(@jpizzuto)
Joined: 1 year ago
Posts: 200
26/07/2020 2:27 am  

@gge

Piqray really made my wife tired.  I thought high ketones would substitute for loss of glucose metabolism.

I took glucose and ketones readings before her evening meal.  Glucose was 101, 102 ish, her last three ketone readings were 2.6, 3.1, and 3.6.

I was watching a Jason Fung video today.  His idea of fasting for health is often criticized as causing loss of muscle, so he was addressing that:  https://youtu.be/rQsMRjAwcFo?t=867

 


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John Pizzuto
(@jpizzuto)
Joined: 1 year ago
Posts: 200
26/07/2020 2:57 am  

Same video, talking about cancer here:  https://youtu.be/rQsMRjAwcFo?t=1757


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Jcancom
(@jcancom)
Joined: 3 years ago
Posts: 434
26/07/2020 4:21 am  

Johan, it is highly interesting to remember that throughout much of the 20th Century stomach cancer was the number one cause of cancer mortality in many nations. What is so highly surprising is that the link between ulcers/stomach cancer and bacteria eluded medicine for decades. Could no one see this connection, even when there was widespread prescription of antibiotics? It is almost unbelievable. Was our entire planet of billions of people truly unable to piece this together. It is very very difficult to believe.

Yet, this is largely the same situation with cancer. Warburg developed the metabolic theory a century ago and surprisingly no one has advanced it through regulatory channels to actually help people. The metabolic ideas that we have discussed for so long likely would be highly recognizable to Warburg.  

 

 


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(@johan)
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26/07/2020 5:17 am  

@jcancom

It would be great to have Otto back, indeed. With so many alternative medicine clinics, I think by now we would have found out if there was a simple elegant solution based on Warburg findings. And in the end, energy is what keeps us alive, and the more energy we have the better our health is, or will be. 

Citrate + NADH + CoQ10 + Nicotinamide + ALA + Malic acid + Pyruvate

Would I want to take this if I had cancer? With what I know today, no. I'd be afraid to give fuel to the cancer cell. But I'd also be giving much-needed fuel to the non-cancerous cells. Which side wins?


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MajorTom
(@majortom)
Joined: 5 months ago
Posts: 9
26/07/2020 10:49 am  

@jcancom

Just to post out that in the 2016 paper from the Basel group, they do not claim that syrosingopine inhibits alpha-enolase activity. It was an unexplained observation why ectopic expression of gamma-enolase (NSE- neutron specific enolase) made cells insensitive to the syrosingopine-metformin combination. This could be useful as a biomarker to indicate which tumors are resistant to the drug treatment.

Enolase activity can be inhibited with sodium fluoride (drinking water and toothpaste), however I assume it would have to be at toxic levels before one can see any appreciable anti-cancer effect. The DePinho group in Texas have generated an enolase inhibitor which they find useful in brain tumours that have are deleted for alpha-enolase (and are surviving purely on gamma-enolase), however this publication is 8 years old and no real progress has been reported. Side effects of enolase or any glycolytic inhibitors may also be severe as glycolysis is the central energy generating pathway used by all cells. A possible combination could be with a ketogenic diet as the ketone bodies can feed the brain by bypassing the glycolytic pathway.


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John Pizzuto
(@jpizzuto)
Joined: 1 year ago
Posts: 200
26/07/2020 11:56 am  

@majortom

I was watching a video a couple days ago that said a ketone reading of 1.5 would supply about 20% of the brain's energy.  My wife was on Piqray for a few days.  She wanted a little pasta for dinner.  An hour after eating, her ketones had dropped from 3.1 to 2.6.  Her glucose went from 101 to 126.  She was very lethargic the next day.


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MajorTom
(@majortom)
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Posts: 9
27/07/2020 1:43 pm  

@jpizzuto The pasta would have supplied carbohydrates to raise serum glucose levels and the nutrient replete condition would have been sensed to reduce ketone body production. Ketogenesis can be artificially induced by switching to a diet consisting almost entirely of fat and protein. However in your wife's frail condition it is best that she should eat what she can to keep her strength up.

PI3K inhibitors have been largely disappointing in cancer. In theory they are very attractive drug targets as they are at the very top of the growth-factor signaling cascade. However, it is precisely because of their general importance that they have unwanted side-effects and toxicity due to systemic effect on normal cells.


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John Pizzuto
(@jpizzuto)
Joined: 1 year ago
Posts: 200
27/07/2020 2:43 pm  

@majortom

I put us both on a very low carb diet two years ago, trying to slow progression.

Her ketone reading was still pretty high.  From what I have read, ketones are readily taken up by brain cells, but the Piqray really knocked her out.  They started her off with a low dose of 200mg, once per day, but it was too much.  I asked her to try taking it every other day, but she's not having it.  

Does 2DG have the same effect?


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GgE
 GgE
(@gge)
Joined: 2 years ago
Posts: 222
27/07/2020 7:47 pm  
Posted by: @manuone

I am going to transfer all these questions to Enoc Pharma and this will be of great interest to all of us.

Have the Enoc Pharma people answered yet?


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Manuone
(@manuone)
Joined: 2 years ago
Posts: 120
28/07/2020 5:06 pm  

Can you post here some links that explain how to use them, what options are available, what the risks are, etc.? https://www.transtechnics.com/index.php?option=com_content&view=article&id=55%3Alosttsomas&catid=34%3Amenuprincipal&lang=es (Only in Spanish. You will have to translate it. I recommend you the translator DeepL, it's the best by far)

I googled some liposome encapsulation and it sounds very interesting. There are many, many questions that come to mind. You may have the answers. I apologize if you've posted them before, but could you explain:

How do we know if the drugs we want to encapsulate are going to damage the liposome before they enter the cells, or if they're not released once inside the cell and they just come out, liposomes and all? Until it is tested, we cannot know if the drug will be compatible with the liposome or not. Part of this compatibility or not only depends on the characteristics of the molecule itself, but also on the ratio of the amount of active ingredient to the amount of liposomes. Liposomes are capable of crossing and diffusing through all types of tissues and organs and are also capable of crossing cell membranes in an integrated manner, i.e. without breaking. The release of the active ingredients from the liposome will occur to a greater or lesser extent depending on many factors such as, for example, the degree of hydrophilicity or lipophilicity of the active ingredient, the different interactions with cells and tissues, the type of cell, the permeability of the cell membranes, the higher or lower temperature, the degree of inflammation, permeation and vascularisation of the tissue or cells, the cell activity, etc. Yes, the active ingredients can be released into the bloodstream, the extracellular space and also into the intracellular space, even into the cell nucleus (transgene). Liposomes are also able to pass through cells, entering and leaving them, even through dead cells such as skin corneocytes.

You love honokiol. Have you encapsulated it in lipo? If so, what was the result?

Could metformin be encapsulated in lipo, delivered primarily to cancer cells and thus avoid the gastrointestinal problems and weight loss it often causes? Yes, like almost all molecules, in its right ratio of active ingredient to number of liposomes, metformin can be encapsulated in liposomes. Liposomes tend to go where there is more cellular activity, such as cancer cells or inflammatory processes of all kinds, and also where there is more cellular or tissue permeability caused by different reasons. Almost always the administration of the active ingredients in liposome form reduces the secondary or undesirable effects of these in a relevant way, among them toxicity, irritation capacity, etc.

Could syrosingopine be encapsulated in lipo, administered mainly to cancer cells and thus avoid the blood pressure drops it usually causes? Yes, as in the previous question, the best ratio of syrosopine to the amount of liposomes must be found. Because of the characteristics and behavior of cancer cells in general, they have the tendency to accumulate or capture 25 to 50 times more liposomes than healthy or normal cells. Although liposomes produced with a high concentration of phosphatidylcholine have a tendency to relax the vascular musculature and "lower" blood pressure, this effect is not very relevant or important. The slower and more selective release of the active ingredient will cause the drop in blood pressure to be less than that produced by the active ingredient in its conventional form.

How can you tell if the molecules of a drug are too big to fit inside a liposome? The liposomes we generally use are about 100 nm in diameter. That is to say, there is room for a significant number of molecules and also quite large molecules. The capacity or not of encapsulation of large molecules will also depend on their characteristics such as their spatial conformation, polarity, etc. and on the place they occupy in the liposome, either incorporated in the liposomal membrane or in the internal aqueous phase.

How can we know how much of a drug can be loaded into a number of empty liposomes? If the drug is purely water-soluble and without any degree of lipophilicity, which is very rare, it will be difficult to know which part of it has been encapsulated or not. In 100 nm liposomes prepared at a concentration of 100 mg/ml of phosphatidylcholine like ours, the internal aqueous phase is between 15-17% of the total volume of the liposome and therefore the amount of encapsulated active ingredient will correspond to these proportions, 15-17% of the total purely water-soluble active ingredient. I must tell you that throughout my experience I have seen very few purely water-soluble molecules or active ingredients, urea, glucose, caffeine, etc. Most of them, although at first they are water-soluble or are considered as such, also have a certain degree of lipophilicity that can become very important, such as, for example, vitamin C (sodium ascorbate) in which the degree of encapsulation is almost 100%. The pH of the liposome solution, the type of salt or base of the drug molecule, chloride, sulphate, lactate, acetate, etc. can also influence the degree of lipophilicity or hydrophobia of the same and, therefore, the effectiveness of encapsulation of the active ingredient. For example, there is a great difference between encapsulating morphine hydrochloride or morphine sulphate. If the medicine is liposoluble the degree of encapsulation, if the ratio quantity of active ingredient/quantity of liposomes is correct, will be 100%. If too much of the drug or active ingredient is added in this case, it will, over time, precipitate or remain as a supernatant. An excessive amount of active ingredient per liposome can lead to the "destruction" of them. In general, it is better not to overload the liposomes: This can be considered a general rule, it is better to have more liposomes with less active ingredient than few liposomes with a lot of active ingredient. To know exactly the encapsulation efficiency of an encapsulated active ingredient in the liposomes, techniques must be used to separate the free, non-encapsulated active ingredient from the encapsulated part in the liposomes. Techniques such as equilibrium dialysis, tangential ultrafiltration, Centrisart system, centrifugation, ultracentrifugation, ion exchange resins, etc. must be used. to later analyze it by the most appropriate method for each molecule and thus know which part is or is not encapsulated, that is, to know the effectiveness of encapsulation.

 

 


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Manuone
(@manuone)
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28/07/2020 5:20 pm  

You say the shaker encapsulates a large portion of the drug. Can you guess a percentage? Is it like 70% or more like 95%? A simple magnetic or paddle shaker is enough to make a good encapsulation of the actives in the liposomes. The percentage of encapsulation will depend on the characteristics of the molecule, the pH, the stirring time especially in little soluble molecules, etc.

Is there a big difference in terms of better results between the magnetic stirrer you use and the expensive ones, or are they simply faster? Any stirrer that is able to remove the liposomal suspension with the active ingredient in dilution or in suspension and create a vortex is suitable for achieving good encapsulation. Normally the price of the agitator is more representative of the quality and power of its motor and also of its average life span as well as of other accessory functions such as the possibility of heating the suspension, timer, etc., than of its encapsulation efficiency. An expensive, good quality agitator usually lasts much longer and can work for several days in a row without any problems

Is there any way to know how much of the drug is not encapsulated without having a lab? With liposoluble products it is, approximately, simpler, since the non-encapsulated part usually precipitates or supernatates. With water-soluble products this is more difficult and separation techniques, mentioned above, and analytical techniques are needed.
Is there a way to remove the non-encapsulated part of the drug? Do you need special instruments to do this? With fat-soluble products the non-encapsulated part that normally precipitates can be separated by simple decantation or by simple filtration with a paper filter. With water-soluble products the issue is more complicated and more complex separation techniques such as those mentioned in the previous questions are needed to know or calculate the encapsulation efficiency of an asset. In general, cooling the formulation in a refrigerator to 4-8ºC accelerates the precipitation of the non-encapsulated part. Do not use the freezer.

If you cannot remove it, is there a way to bind or neutralize the non-encapsulated part of the drug and avoid taking it, without damaging the encapsulated part? If it cannot be removed by simple decanting or filtration with paper, the way to separate the encapsulated part from the non-encapsulated part should be done by the same methods of separation as in the previous questions I mentioned. Neutralizing it is very complicated and there would always be the doubts of whether the "neutralizer" has not affected the encapsulated part or even if the neutralizer has also been encapsulated, so I would have to analyze it. Changing the pH of the liposome suspension until the free active ingredient, normally in the form of salt, becomes insoluble and precipitates would be one of the simplest ways of doing this, but there would always be the doubt as to whether this manoeuvre has affected the encapsulated part. Anyway, knowing that the degree of potentiation of the activity of the encapsulated part is much greater, more active or powerful than that of the free part this should not mean a serious problem in the majority of cases, unless it has been greatly exceeded with it. In some cases, depending on the type of active ingredient and the activity sought, it may even be convenient or beneficial as it can achieve a rapid effect produced by the free part and a more delayed and prolonged effect produced by the liposome part of the active ingredient. 

How do you prevent the liposomes you propose to use from becoming trapped in the liver or eaten by the mononuclear phagocyte system? By making the organism believe that these have been produced by it.  

How do these liposomes pass through the acids of the stomach and the intestinal digestive fluids? Absorb into the intestine without being damaged; leave the blood vessels near the tumors; infiltrate the hostile tumor microenvironment, penetrate inside the cancer cells and release the anti-cancer drugs without causing damage to normal cells? These are many questions together and somewhat disparate. To summarize it in one answer, the key is to make very flexible liposomes, adaptable to changes in the environment and its conditions or characteristics, such as changes in pH, polarity of the environment, ionic and osmolar conditions, etc.

How do they reach the cancer cells found in large tumours, away from the blood vessels? By the same condition I mentioned in the previous answer, since these characteristics of the liposome mentioned in my previous answer give it the possibility to circulate, penetrate and spread through all types of tissues and organs without losing its integrity, for example the passage of the blood-brain barrier, the skin barrier, etc.

Do these liposomes contain PEG polymers? No, our liposomes do not contain PEG. We only use PEG to anchor antibodies to the liposomal membrane and to achieve a very specific targeting by binding PEG to the phosphatidylethanolamins (PE) previously incorporated in the liposomal membrane and then anchoring the antibody to that PEG. Normally other technologies use PEG to "camouflage" the liposomes of the immune system, preventing it from detecting and "eliminating" them and thus achieving a longer circulation time. We use the system to make the body believe that it has produced them and that they belong to it, just as it produces many types of vesicles, such as presynaptic, hepatic and other vesicles that the body is capable of producing.  
 
Did you choose Enoch Pharma because they are local to you? Do you know of equally good or even better companies in the United States?
You said you trust the scientist who develops these liposomes. Can you share some information about him?
Which of Enoch's liposomes are you using? How much do they cost?
Have these liposomes been proven safe or used in clinical trials? Yes, the safety of these liposomes "per se", during my 35 years of experience with them has been proven in many occasions and conditions, by all the therapeutic routes of administration and at many concentrations and dosages. Not even by injecting 4 times the volume scientifically permitted in the scientifically established regulations and conditions have we been able to achieve a lethal dose of 50 (DL/50) with the same, empty liposomes. That is to say, no mouse or other experimental animal has ever died on us and, of course, no person or patient, by administering our empty liposomes. These, as well as all their components, have the condition of GRAS (Generally Regarded As Safe) and comply with all the requirements of pharmaceutical regulations.
Can you share Internet links to documents you consider important for people who are thinking of adopting this technology, in addition to Enoc Pharma?

Do you know of any ways to use exosomes on this link? Https://jnanobiotechnology.biomedcentral.com/articles/10.1186/s12951-019-0517-8 No, I do not. When I have time, I will look at it and, if necessary, comment or give my opinion.

 

@GgE Here are the most relevant questions and answers about empty liposomes that I have received from Enoch Pharma.
The translation has been "literal" with an online translator so sorry for the bad English.
In the link to the transtechnics.com website there are detailed encapsulation processes (was the old Enoc Pharma)

Kind regards


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Jcancom
(@jcancom)
Joined: 3 years ago
Posts: 434
29/07/2020 1:05 am  

Manuone, this is a remarkable step forward for the forum! Thank you!

It is almost hard to imagine how far off we have been. Liposomes loaded with a wide range of active ingredients could be of truly enormous importance for many on forum. Hopefully, we will  be able to move away from unformulated treatments (e.g., with syrosingopine) which typically have dose limiting side-effects. With good formulations we could potentially both down dose and achieve better therapeutic results simultaneously. What is further remarkable about the liposomes that you have referenced is how easy they appear to be to load. Basically stir? This is a great step forward. Our goal should be to formulate all treatments. It is quite surprising to me that typical FDA drugs are not formulated with liposomes. The absurd idea emerges that proper medical care would require patients to bring their medicines home and stir them in their conditions to make DIY liposomes. How could this possibly be sensible? At the least it should be widely known that compounding pharmacies would be available to formulate medicines as needed by patients.

I will be interested to know about formulating ionic type treatments such as metformin and mito-HK. These treatments already have considerable cancer cell specificity. Would formulating them in liposomes increase this selectivity? I would be worried that a charged molecule might want to escape the liposome as soon as possible, perhaps defeating their purpose.

There are a great number of exciting applications to try. For example, perhaps liposomes could be loaded with synergistic combination treatments. Even still it might be advisable to be somewhat cautious about dosing with some of the more powerful treatments that we have investigated. I am not entirely sure how syrosingopine might behave when administered as a liposome. Would it penetrate the BBB? Might it somehow become overly concentrated in certain cells and cause side effects? There is a great deal of use and research that suggests that these are not realized problems, though it might still be wise to be careful. There are so many potential substances to liposomalize (e.g., vitamin C, methylglyoxal, citrate, honokiol, ... ... ) that it should not feel constricting.

Chitosan, though, might continue to offer advantages as a nanoparticle vehicle. Perhaps gaining knowledge with liposomes could allow us to gain confidence to also try additional formulations including with chitosan.

 

 


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GgE
 GgE
(@gge)
Joined: 2 years ago
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29/07/2020 9:24 am  
Posted by: @manuone

Here are the most relevant questions and answers about empty liposomes that I have received from Enoch Pharma.

Thanks so much for this "Liposome 101" course you posted. We can learn a lot from it.

Please keep posting here if and when you can answer the rest of the questions. Every little bit helps.


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Jcancom
(@jcancom)
Joined: 3 years ago
Posts: 434
30/07/2020 1:13 am  

Encapsulation/formulation is a great advance in our understanding of how to effectively treat cancer. It is somewhat surprising that even those with fairly high level understanding of cancer have also made the mistake of treating with non-formulated therapies. What this demonstrates is that multiple skill sets are required to create effective treatments; such multiple skill sets are rarely all present in a given person, so it can either take one person a very substantial amount of time to explore the entire landscape of skills needed or a team effort in which these skills can be explored by many people possibly over a significantly shorter amount of time.

I greatly wish that others on forum also share my enthusiasm for this latest development. By collectively exploring the many variables involved in formulation we can find the tricks that will allow for optimization.

 

 


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Daniel
(@daniel)
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31/07/2020 2:22 am  

@jcancom Yes J, time is a big issue for those fighting cancer. You need to deal with so many things at the same time ... so we end up picking the low hanging fruits when trying to find a solution to cancer.

Formulating a drug is not easy although it may sound easy in some cases. You need to make sure that you create a formulation that dose the job better than unformulated, and is at the same time safe when applied.

I remember how much time it took me to find the right way to formulate Salinomycin and define the steps for implementation in a safe manner. It would have taken so much more time to get to a more advanced form. Having the support of a team with experience to help you gain time is essential in this case.


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Jcancom
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31/07/2020 2:45 am  

MajorTom, thank you for replying and correcting my comment about alpha-enolase. Hmm, that is somewhat confusing; syrosingopine binds alpha-enolase though does not actually inhibit it? Yet, it might work through other pathways? in vitro might not accurately duplicate what happens in vivo?

I am glad that you noted that glycolysis inhibitors might have severe side-effects. This possibly is the line of thought that has discouraged much of the interest by pharmaceutical companies in metabolic approaches. Basically, shutting down glycolysis would cure cancer, but if done non-selectively the patient would not survive the treatment. It is good to speak in a more basic form so that we can talk directly to these arguments and not have them quietly shifting the conversation. Yet, through decades of metabolic research an ever increasing number of treatment approaches have been developed that are able to apply metabolic stress selectively to cancer cells. 

3-BP is a notable example. Even when given largely in an unformulated state 3-BP has selective cancer cell entry due to the acidic cancer environment, the upregulation of MCT-1 etc.. The notion that cancer cells are too close to normal cells to be targeted has been shown on multiple occasions to be incorrect. It surprises me, in fact, how many such differences exist. The example of E260 (OXPHOS I inhibitor) is an especially notable example. Cancer cell ETC include a protein that is used almost nowhere else in the body. Our current interest in proper formulation might also help redefine the discussion as treatments might be directed in a focused manner to the cancer and not other cells.

While it is true that the glycolytic enzymes still pose somewhat of a logistical challenge for metabolic treatment (especially with respect to unformulated treatment), given the highly overactive nature of glycolysis in cancer and the large amount of lactate production etc., there are a range of highly attractive targets that are directly on this pathway or closely proximal to it. 


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GgE
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31/07/2020 7:34 pm  

An interesting 2020 article:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352845/

Tracing Nutrient Flux Following Monocarboxylate Transporter-1 Inhibition with AZD3965


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Jcancom
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01/08/2020 1:38 am  

GgE, the idea that some cancer cells can import lactate and then oxidize it in the TCA cycle has only become more definitively established fairly recently. https://pubmed.ncbi.nlm.nih.gov/28985563/   As seen below (another very informative figure) there is an ingenious logic involved.

Namely, the cancer cells near the blood vessels ("near" cells) have access to oxygen, so they can cooperate with the tumor cells further into the tumor ("far" cells) which lack access to oxygen. The "near" cells can do this by foregoing glucose in order that the "far" cells can be hyperglycolytic. The "far" cells then pass forward lactate to the "near" cells which can be oxidized in the TCA and then in OXPHOS. A fairly interesting symbiotic strategy. This is a reasonably deducible inference because where there is no oxygen there can be no OXHPOS. It must be true!

However, as shown on the right below shutting off MCT1 entry of lactate to the "near" cells forces them to take up glucose. The "far" cells have just lost their meal ticket resulting in their necrosis. Perhaps treating with OXPHOS inhibitors might then be a powerful combination; it would force the near cells to be exclusively hyperglycolytic and thereby compelling them to gobble up all the nearby glucose (further depriving the "far" cells of glucose.)

This could be quite a powerful strategy because these "near" cells basically occupy the high ground. They have first choice at the buffet. If they block off the glucose supply to the "far" cells (and ironically export lactate to these "far" cells), then the hypoxic cells would get a taste of their own medicine.

Even still these hypoxic cells that must rely on glucose because of their hypoxic environment is one of the bigger mysteries for me about cancer. They are so egregiously villainous that I really wonder why a treatment has not been developed to remove them. One idea that suggested using anaerobic bacteria seemed like a plausible place to start.    

 

 

https://pubmed.ncbi.nlm.nih.gov/19033663/


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GgE
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01/08/2020 8:40 am  
Posted by: @jcancom

However, as shown on the right below shutting off MCT1 entry of lactate to the "near" cells forces them to take up glucose. The "far" cells have just lost their meal ticket resulting in their necrosis. Perhaps treating with OXPHOS inhibitors might then be a powerful combination; it would force the near cells to be exclusively hyperglycolytic and thereby compelling them to gobble up all the nearby glucose (further depriving the "far" cells of glucose.)

What do you do once you have killed the hypoxic far cells? How do you kill the near cells so that they don't proliferate and replace the dead cells and allow the cancer to continue progressing?


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Jcancom
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01/08/2020 4:30 pm  

GgE, thank you for returning to this important point; unfortunately we have entered an age more of the discursive than of discourse.

If nothing else removing the hypoxic tumor mass would simplify the problem of cancer. The logic that I gave above shows that a symbiosis can emerge between the "near" and "far" cells. Removing the "far" cells would remove one layer of complexity. The importance of reducing the complexity of problems when possible should not be casually dismissed.

Yet, clearly the hypoxic mass does much more than that. These hypoxic cells are obligate lactate producers. The excessive lactate of cancer causes endless problems. I am not entirely clear whether cancer could be cancer as we know it now without such an overwhelming supply of lactate. Lactate is what allows 3-BP to enter cells; in fact 3-BP can be described roughly as a lactate analog.  

The hypoxic mass is also likely the great majority of cancer cells. As the cancer grows from the blood vessels, the tumor below is submerged farther and farther away from its nutrient supply. The disfigurement and probably much of the pain that can occur with cancer are related to this submerged mass. It is disappointing to me that treatments have not emerged to address these hypoxic cells. The difficulties they cause should reasonably allow for a lower bar of evidence than survival to be used for their regulatory approval. Using the standard of cosmetic appearance or level of pain as the measure of success might entice companies to develop such treatments when survival endpoints can often be elusive especially when the treatment is given as monotherapy.

Realistically it would not seem that unlikely that an anti-hypoxic therapy could be developed. Hypoxic cancer cells are extremely different from almost any other in the body. The anaerobic bacteria approach illustrates how these biological differences might be open to targeting.   

 

   


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Jcancom
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02/08/2020 11:47 pm  

GgE, over the last week my understanding of how to manage cancer has been improving. One of the highlights has been a deeper appreciation of the power of oncolytic viruses. I had not focused enough of my attention on the idea that OVs selectively infect cancer. Selectivity is perhaps the central challenge involved with cancer. The fact that as an entire class of treatment OVs offer such selectivity is quite extraordinary.

I mentioned above about the attacking the necrotic areas of the tumors my thinking was partly inspired by the results with Clostridium novyi-NT. In mice research curative responses occured with CN-NT treatment. Removing the necrotic area truly is a powerful approach. One of the articles noted that the motility of the bacteria is as if you had little robots moving through the tumor mass. Would be interesting if they could load up the bacteria with oncolytic viruses.

Another idea that I found quite provocative was that apparently CN-NT release an enzyme that can cause liposomes to release their drug treating cargo! That could be quite helpful. I was unable to find references about cancer specific conditions that might trigger liposomal release in the comments above. On the website they spoke proudly of how liposomes maintain their integral down to ~5.5. With cancer cells it would actually be therapeutic if they were to degrade ~pH 6.8 or less. 

http://www.cancerjournal.net/article.asp?issn=0973-1482;year=2018;volume=14;issue=8;spage=1;epage=6;aulast=Wang

 

 

 

 

 


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