Whenever i see nano particles used to combat disease, I am always interested in the off target controls. Since they are using physical mechanism to disrupt membrane stability (in the case of bacteria), controlling targeting is very difficult and requires vastly different membrane properties on the surface of bacteria vs regular cells. Issues usually involve lodging of nano particles in the liver or kidneys/ lysis and cytotoxicity . Here they looked at haemolytic and necrotic activities in cells and assessed whether the mice survived- most are short term, and aggregation of nano particles is not uncommon to cause large obvious pathology, it just takes time.
I looked up the core molecule 'PAMAM' or Poly(amidoamine) and it seems to show relatively low cytoxicity, but recent studies seem to shed some more light:
'More recently, a series of studies by Mukherjee et al.[13][14][15] have shed some light on the mechanism of PAMAM cytotoxicity, providing evidence that the dendrimers break free of their encapsulating membrane (endosome) after being absorbed by the cell, causing harm to the cell's mitochondria and eventually leading to cell death. Further elucidation of the mechanism of PAMAM cytotoxicity would help resolve the dispute as to precisely how toxic the dendrimers are.'
Seems so. Results are conflicting in terms of adverse effects. But seem to show these particles cross into normal cells (neurons for example)/ some lead to death some do not.
here is a quote though from one paper in mice at high concentrations:
'There was no effect on other haematological parameters. Histopathological evaluation of dendrimer-treated groups did not reveal any abnormalities in the low- and medium-dose groups, but at a high dose level, toxicity was observed in the liver and kidney.'
Looks like they found a way to generate nanoparticles that don't damage
host cells, but target bacteria more or less exclusively:
These star nanoparticles were termed ‘structurally nanoengineered
antimicrobial peptide polymers’ (SNAPPs). Unlike existing selfassembled
antimicrobial macromolecules, which will dissociate to
unimers below their critical micelle concentration, SNAPPs
are stable unimolecular architectures up to infinite dilution. We
demonstrate that SNAPPs exhibit superior antibacterial activity
against a range of clinically important Gram-negative bacteria,
possess high therapeutic indices and display selectivity towards
pathogens over mammalian cells.
More on biocompatibility with humans:
As a test of biocompatibility, the haemolytic activities of SNAPPs
were investigated by incubating them with red blood cells at different
nanoparticle concentrations. Both S16 and S32 had negligible
haemolytic activity. Even at a very high concentration of >100 × MBC,
the extent of haemolysis was well below 30%. Subsequently, we
investigated the viability of two types of mammalian cells (human
embryonic kidney cells and rat hepatoma cells) in response to SNAPPs.
The therapeutic indices (TI) of SNAPPs ranged from 52 to 171 ,
generally higher than the TI of colistin, which is currently being
used as the last therapeutic option for MDR Gram-negative pathogens
Very promising stuff. Even though this was built as a treatment for
gram-negative bacteria, it seems to show an effect for gram-positive
bacteria, too. Equally promising is how uniformly effective SNAPPs
seemed to be across several types of gram-negative bacteria.
It would seem very hard as the main mechanism of action for these nano particles is electrostatic pore formations- confirmed by their mechanistic studies.
This would require evolution of the outer membrane (OM), quite a big change for a bacteria to evolve. That said it's very surprising there are so few off target effects.
To some degree there are things that are "resistance proof", in that forming resistance to them would defacto leave organisms unable to survive in the human body.
A good example is highly acid/basic environments, thermal stress, or alcohols and solvents.
Anything that can reproduce in a 50 degree C alcohol bath, for example, is going to have a tough time adapting to humans well enough to be pathogenic.
These polymers might be a similar phenomenon, but that would also imply that they're inimical to humanity too, though perhaps at a higher concentration.
Don't forget prions. They survive temperatures above 120C and also alcohol and remain infectious. (Hydrogen peroxide and alkalis seem too work, but see [1] because I really know nothing of the science of sterilization.)
Prions, like viruses, reproduce when inside a host. Parasites, bacteria, fungi, viruses and prions are all types of pathogens.
Sterilization protocols need to be followed to ensure that one patients prions don't infect another surgery patient. It turns out that relatively recent concerns over transmissible spongiform encephalopathy, caused by prions, has required changes to the sterilization procedures used in hospitals.
the fact that the polymers don't kill the mammalian cells means that whatever mammalian cells do to avoid destruction can be adapted by bacterial cells for their survival.
That's not true. Antifungals target ergosterol, which is a cell membrane compound (fungal cholesterol). Also the side effects are likely due to the similarities between ergosterol and cholesterol.
Vacuoles would probably be a good solution, or some means of transport back out of the cell, and both would probably be minor modifications of existing systems in bacteria. I wonder if either would increase the stress on the host as well.
Destroying diseases through biomechanical stress sounds cool. But my concern would be whether the stress increases the mutation rate. As a well-known example of another biomechanical stress that does so, consider asbestos.
I wouldn't want a treatment for my cold that could give me cancer in 20 years...
ummm. The cold is caused by a virus (rhinovirus, RSV, enterovirus, or adenovirus) not bacteria.
Please don't take antibiotics to treat viral infections. The best you can hope for is (measurable) damage to your own gut bacteria. The worst is breeding more superbugs.
The common cold is indeed caused by a virus. However colds often result in opportunistic bacterial infections, and a very large number of what people call colds are caused by bacteria.
Therefore many (though certainly not all) colds are appropriately treated with an antibiotic.
I know next to nothing about this stuff but is using antibiotics or the kind of treatment outlined in this article prevent our body's natural defenses from "learning" how to fight off these bacterias? Are we basically pumping our bodies full of chemicals to the point that our immune system atrophies after several generations?
A bacterium does a series of chemical transformations to stay alive.
An antibiotic disrupts the bacteria lifecycle by interfering with such transformations.
These transformations might be different across bacteria. As you have millions of bacteria in an individual, some might suffer smaller results from the antibiotic, and be 'not as disrupted'.
If you don't take the full dose of antibiotics, these 'not as disrupted' bacteria might survive, make you sick again. And worse: the antibiotic will have a harder time killing them.
Some of their 'children' will be more 'disruptable' then they are, some less, but the average is less 'disruptable'.
Repeat the process many times, and you get bacteria that don't die with the antibiotic :(
Nothing to do with your immune system, that creates its own kind of 'antibiotic'
Basically they're shooting nano bullets to the bacteria and those bullets can't be stopped. But how can they deliver those nano particles only to the harmful bacteria? They should kill also the good ones.
Phages are being researched. This literally comes up in every single HN thread on antibiotics, so once more, posting my "Why Phages Aren't the Answer" shortlist. Note that I love phage therapy - this is the problems as seen by someone who doesn't think it's a dead end:
Phage therapy is neat, it really is, but there are a couple major issues:
- There is no such thing as a "broad spectrum" phage. You can't do empirical treatment using phages, and there's not really "off the shelf" phage therapy - it tends to be a bespoke creation for a particular infection.
- There's some serious regulatory problems, similar to those experienced by fecal transplant treatments. We're not yet really equipped to think about handling evolving, custom microbes as a treatment. - Because of the first, it's going to require a considerable amount more lab capacity than most clinical settings currently have, and considerable delays until treatment.
- There's also some biosafety issues around phage prep, but those are easily solvable.
It's a great way to treat particularly resistant or hard to treat infections, but it's not a particularly great general solution. There's a reason it was abandoned in countries with easy access to antibiotics - they're just roundly superior in basically every respect.
I looked up the core molecule 'PAMAM' or Poly(amidoamine) and it seems to show relatively low cytoxicity, but recent studies seem to shed some more light:
'More recently, a series of studies by Mukherjee et al.[13][14][15] have shed some light on the mechanism of PAMAM cytotoxicity, providing evidence that the dendrimers break free of their encapsulating membrane (endosome) after being absorbed by the cell, causing harm to the cell's mitochondria and eventually leading to cell death. Further elucidation of the mechanism of PAMAM cytotoxicity would help resolve the dispute as to precisely how toxic the dendrimers are.'
[0]https://en.wikipedia.org/wiki/Poly(amidoamine)#Toxicity