RNA-Loaded Nanoparticles Fight Cancer

DirkDaring writes "It's been promised for years: that nanoparticles offer a treatment to many forms of cancer. Today, an important first step has been announced. In a new human trial, nanoparticles carrying RNA have successfully reached cancer cells and silenced the target gene. 'The researchers developed a nanoparticle carrying a molecular marker that binds to the surface of cancer cells, triggering the cells to absorb it. The siRNA carried within the particle was designed to silence a gene called ribonucleotide reductase M2 (RRM2), which regulates DNA synthesis and repair and is known to be an anticancer target. Because it was the first trial using targeted RNAi delivery for cancer, says Mark Davis, a professor of chemical engineering at Caltech and the study's lead author, "we wanted to choose a gene that was suspected to be hugely upregulated in a broad spectrum of cancers" in order to increase the likelihood of being able to observe the novel therapy's effect. The researchers analyzed biopsy samples from three melanoma patients in the trial who had received different doses of the therapy. They tracked the particles in the different samples, finding that the amounts they could see in the tumor cells correlated with the doses the patients received.'"

Comments

Interesting article

[mcgrew]

I wonder if this technique could be used for other diseases, e.g. arthritis?

Re:Interesting article

[Anonymous Coward]

HIV, AIDS?

Re:Interesting article

[Anonymous Coward]

i think can be used for other diseases so long as we are able to isolate the gene that causes the disease. I would suggest looking at the Human Genome Project to see what genes have been mapped and isolated as the cuase of various diseases.

Re:Interesting article

[AlexBirch]

This is a bit dated, Sirna was acquired by Merck for this kind of technology over 2 years ago. Alnylam is yet another large player in this game.
Arthritis is a bit more difficult due to delivery issues and known pathways

Re:Interesting article

[AlexBirch]

HIV mutates very frequently, so it's difficult to design an siRNA reagent to target it effectively. Another hurdle is delivering the siRNA to the infected T cells.

Re:Interesting article

[reverseengineer]

This could be an especially attractive method of delivering treatment for rheumatoid arthritis if it could be made to work. As an example, among the current state of the art in rheumatoid arthritis treatment is rituximab. Rituximab is an engineered mouse/human chimeric monoclonal antibody that targets CD20, a protein unique to B-lymphocytes, whose overactivity is a major factor of RA. Because it is a monoclonal antibody, it is very expensive, and short-lived in the body. The nanoparticles used in this cancer study were made from starch and polyethylene glycol. All rituximab can really do to B cells is kill them, which gets the job done, but can leave the patient with serious immunological vulnerabilities. A more sophisticated treatment would be to use CD20-targeted nanoparticles to bind to B cells and deliver a package of siRNA that interferes selectively with the transcription/translation of genes involved only in the autoimmunity.

Re:Interesting article

[thechao]

Yes. There is a large focus on two different aspects in a lab I used to work with a few years ago:
(1) Retinopathies (problems of the eye);
(2) Preventative treatments for cancer.

Here are some links:
[1] http://inbt.jhu.edu/biosensor-targets-retina-cells/2006/11/15 -- a multilayer "machine" which executes a biochemical program;
[2] http://nanohub.org/resources/3541/download/2007.10.15-leary-nt501.pdf -- lecture notes on the state-of-the-art nano- magneto- and silicon particle drug delivery as of late 2007.

Re:Interesting article

[interkin3tic]

I wonder if this technique could be used for other diseases, e.g. arthritis?

It could be useful for other diseases in which a gene is known to be expressed that you don't want to be expressed. Whether there are known genes which are expressed with arthritis that cause the symptoms, I don't know. Whether this technique will be effective at delivering the RNAi to other cells using other receptors, I don't know, and I'm not sure anyone knows. I gather that they tried this first, they had to have tested this in mice first, I'd expect there would be data on knocking down genes in non-cancerous tissues.

Shorter answer: maybe, but using this to deliver the treatment to your knuckle cells to treat arthritis might not work, and for all I know, the RNAi treatment itself might not be viable for treating arthritis.

Re:what if it wins...

[gomiam]

Since the marker attaches to cancerous cells only, healthy ones should suffer no damage. Then again, I read the story above, so it's not like I'm specially insightful.

most isn't good enough

[Anonymous Coward]

Cancer evolves and grows rapidly. Kill 90% of a tumor, and the 10% can grow to be a problem again.

Re:most isn't good enough

[mcgrew]

That's the beauty of this technique. With other therapies like chemo, surgery, or radiation, there is damage to non-cancerous tissue, and those don't kill 100% of the cancer, either. With this you could theoretically continue treatment, as with traditional treatments you can't.

There is still the problem of diagnosing the cancer early enough; this wouln't have helped Linda.

Re:most isn't good enough

[Mindcontrolled]

Aside from oversaturating target cells with specific drugs, you would probably use a combination approach - use different surface markers to guide the nanoparticles and use different targets for the siRNAs, so that even with the high mutation rate of cancer cells, the population as whole can't escape.

Re:most isn't good enough

[chihowa]

... and those don't kill 100% of the cancer...

In this case, you're still only killing the cancer cells that a) express this particular biomarker and b) are capable of/"willing to" take these nanoparticles from the surface of the cell to the inside where they can do their thing.

There's still plenty of room here for treatment resistant cancer cells to survive or develop. RNAi is a great therapeutic approach, but it's no magic bullet. It is terribly attractive, though, because it's easier to develop RNAi that's targeted for specific diseases than it is to develop effective small molecule drugs. The big hurdle to date has been effective delivery of the RNAi. You can't exactly flood the body with it like most drugs. Of course, an effective delivery system like this can allow the use of powerful drugs without some of the horrible side effects.

Re:most isn't good enough

[Anonymous Coward]

No, the point is cancer cells evolve faster than we can understand the proteins they express. The patient is welcome to continue treatment, but the RNA won't bind to the evolved cells (cell epitopes change), so the patient dies from cancer in the long run anyway. Knocking out 100% of the cancer isn't impossible, but it's not probable.

And if, for instance, the patient has brain cancer, it's probably going to be difficult continuously getting samples of the cancer so treatments can coevolve with the cancer. The immune system is good at evolving quickly, which is one of the reasons immunotherapy is so promising.

Unfortunately, as the patient ages, their immune system will become ever more ineffective for a number of reasons.

One way to get your head around all the problems with aging, and how to neutralize them, is http://en.wikipedia.org/wiki/Strategies_for_Engineered_Negligible_Senescence

Unfortunately, the SENS way of dealing with cancer destroys every cell's ability to lengthen its own telomeres. That's fine for guaranteeing you won't develop cancer (now even your cancer cells can only divide a finite number of times) , but the patient should be ready for life-long stem cell infusions for the bone marrow, gut, and elsewhere. So perhaps if the disease doesn't kill the patient, the treatment will.

Re:what if it wins...

[Mindcontrolled]

The most interesting part here is not about directing damage, it is that this was a successful non-topical application of siRNAs. In most tests up to now, siRNAs have been injected directly into the target tissue. This study shows a delivery system that carries the siRNA specifically into targeted cells via the bloodstream. In the long run, this might be the key to target metastases however small they are and wherever they are.

Great... not filtered out by the body

[Orga]

From TFA: "researchers have struggled to design particles that carry their contents to target cells with enough specificity, or that don't cause toxicity or elicit an immune reaction from the body." So when can we: a. Make this create cancer, or simply destroy cells b. Add these particles to a cities water supply c. Alter a contagious host virus to create them.

Re:Great... not filtered out by the body

[Mindcontrolled]

If you just want to do damage, why would you need a cell-specific targeting system?

Re:Great... not filtered out by the body

[Orga]

Gene specific targeting actually.

Re:Great... not filtered out by the body

[Tanktalus]

Because nuking enemy territory from space, while the only way to be sure, might be a bit obvious as to the source. Merely poisoning their water supply with a cancer-creating virus would be far less obvious.

</cynicism>

Re:Great... not filtered out by the body

[Mindcontrolled]

This is getting a bit too... weird. Also, I'd like to stay off the no-fly list... However, let me say as much that I think this would be a classical case of overengineering for the stated goal. Besides - gene targeting of specific populations won't work with our current state of knowledge. Such groups are not identified by single genes, thankfully. And, anyway, as you said, you gotta be sure, so, the orbit it has to be.

What if cancer cells are a symptom?

[Yaddoshi]

Maybe I'm going out on a limb here, since I practically no medical schooling, but there have been suggestions by certain medical professionals (names elude me at the moment) that cancer cells could be the body's final (and potentially fatal) attempt to correct other, seemingly unrelated health issues. This would also explain why cancer can return after it has gone into remission.

If so, while this technique would stop the cancer cells from spreading, it may not address the cause of the cancer. I suppose we'll find out if/once the treatment becomes mainstream.

Re:What if cancer cells are a symptom?

[Orga]

Cancer is simply a mistake in the copying process of cells. Typically this is brought on by aging, most old people have some cancer in them even if it doesn't end up being the thing that kills them. Since human reproduction occurs under 40 years or so cancer resistance is not something we've improved with evolution. If humans reproduced at the age of 10 we'd probably see cancers develop in our 20 and 30's. If humans reproduced in the 80-90's we wouldn't see cancers until we're in our 100's. It's simply a fact of our reproduction system and evolution that we've developed little reason to exist after our reproductive cycle has ended and therefore our bodies fail us.

Re:What if cancer cells are a symptom?

[Orga]

Actually I'll add to that and say that cancer could be seen as a benefit to our species. Having a faster reproductive rate increases the spread of our genes and therefore quickening our evolutionary rate as a species, in a world of limited resources it's best to kill off the resource consumers who can no longer produce offspring. Nature and evolution aren't here to benefit your grandparents... sorry.

Re:What if cancer cells are a symptom?

[Tiger4]

The current thinking on cancer is that it can be caused by quite a lot of things. Radiation (e.g. xrays or sunlight), chemicals (e.g. cigarette smoke, solvents, adhesives, fuels, a whole library of other industrial chemicals, and even stuff in your last soda pop), viruses (e.g. cervical cancer), or just plain bad luck (mutation of fragile genetics).

Why you body might kick off a cancer to prevent something else is kind of mind boggling. Certainly it might be *possible* that something wacky like that could happen, but the evolutionary indicators run strongly against it. The "something else" would have to be even worse than trying to fight the cancer with all-natural means, and what in hell could that be?

Re:What if cancer cells are a symptom?

[thms]

But if you, as a grandparent, can ensure the survival of your children and grandchildren, then mutations which elongate life make sense again, especially for species that rely on learned behaviour more than instincts.

As for cancer, I still assume that the cancer rate is coupled with the general mutation rate. If your species becomes too perfect in copying it's genes then it might be cancer-proof. But that also means that no changes occur in the germ line - you just became a static species! That mean you will probably die out because everyone else around you still evolves (the Red Queen's race). To summarize: Cancer and evolution have the same molecular basis! I wonder how this stabilized in living fossils....

Re:What if cancer cells are a symptom?

[thms]

Certainly it might be *possible* [...]

Yes, as a true scientist that is the correct answer, and here lies the problem: This non-denial gives this idea all the credibility it needs to run off as pseudo science. And once again the following holds:

The trouble with the world is that the stupid are cocksure and the intelligent are full of doubt. --Bertrand Russell

Re:What if cancer cells are a symptom?

[Ledgem]

The reason why many cancers return after their initial removal has to do with cancer cell types. Previously it was believed that cancer was cancer and all cells were the same, but it is now believed that there are "cancer stem cells." These are cells that bud off into the fast-growing cells that make up tumors, but by comparison the stem cells are slow-dividing and may not fully resemble the tumor cells.

The reason why this is important is because many therapies are designed to target fast-dividing cells. Cells are most vulnerable to treatments (whether chemical or radiation) when they're actively replicating. Chemotherapy does a number on your entire body, but it hits the cancer cells a bit harder because they're dividing even faster. However, even if you clear out a tumor, remission may still occur if the cancer stem cells weren't taken out, as well. And due to their slow-dividing nature, many therapies that we're currently utilizing are likely missing them.

I've never heard of the theory that you mentioned. It seems very unlikely that cancers are intentionally brought about by the body, given that we have essentially no examples of cancers being beneficial, and from what we know of cellular biology there are many, many factors designed to guard against cells becoming cancerous.

Re:What if cancer cells are a symptom?

[Hurricane78]

What the hell? OF COURSE cancer cells are a symptom!
Yes, ever if your doctor lies to you by telling you something different.

The original cause is ALWAYS either generic, or ultimately coming from the outside. That’s it. Period.
Radiation causes cancer. Aspartame causes cancer. A dirty environment (smog) causes cancer. Smoking causes cancer. And so on.
Cancer is a result of something else. Always.

It’s a shame that nowadays even a doc will tell you with a straight face, that some organ is the cause. As if it were the ultimate cause. They will even call the headache the cause, when you bang your head against a wall all day long. But they will not tell you to do that. (Won’t continue making them any money, now would it?)

Re:What if cancer cells are a symptom?

[Hurricane78]

You seem to ignore radiation, Aspartame, pollution/smog. smoking, and a billion other things.

Re:What if cancer cells are a symptom?

[Hurricane78]

Protip: One word: Alcohol!!

I Am Legend

[lymond01]

TV Personality: And how many people have you treated so far?
Dr. Alice Krippin: Well, we've had ten thousand and nine clinical trials in humans so far.
TV Personality: And how many are cancer-free?
Dr. Alice Krippin: Ten thousand and nine.
TV Personality: So you have actually cured cancer.
Dr. Alice Krippin: Yes, yes... yes, we have.

Cue destruction of humanity by albino gymnasts.

Re:What if cancer cells are a symptom? pseudosci.!

[Anonymous Coward]

have been suggestions [..] certain medical professionals [..] could be

That are too many weasel words, and I raise a pseudo science alert! While I don't claim to know better, taking a potshot at conventional medicine with a very vague concept is not helpful.

Also, cancer cells are no longer within the normal parameters of human cells and mutate wildly, please suggest how they could be in any way helpful.

Something doesn't add up here.

[Schickeneder]

So they say this has the ability to silence genes. Yet the article says the treatment accomplished its purpose of splicing mRNA. Splicing mRNA!=gene silencing. This would mean this is a dose-dependent, reversible effect and not a permanent treatment. That makes it sound like someone would have to continually be on the drugs and when they stopped, then the effect would disappear and everything would return to pre-treatment conditions. During that time what's to stop the cancer from mutating and losing or altering those specific receptors.

I may have to actually read the primary literature, the summary article did a poor job of explaining any of this.

Re:Something doesn't add up here.

[Schickeneder]

Oops

edit: splicing mRNA = post-transcriptional gene silencing

Re:Something doesn't add up here.

[Orga]

Helllllo for profit healthcare. Nobody wants to cure you, they just want to be able to treat you for longer.

Re:Something doesn't add up here.

[reverseengineer]

Well, yes and no. You are absolutely right in that this isn't a permanent effect, in the sense that the DNA of the cancer cells is not altered at all. RNA interference is like putting a defender in the game to intercept a pass; if the defender leaves the field, the receiver will be open again. Translation of the ribonucleotide reductase gene will only be blocked as long as the interfering RNA is there to block the messenger RNA. However, ribonucleotide reductase is incredibly important; it's the enzyme that tears a hydroxyl group off of ribonucleotides and makes them deoxyribonucleotides. A cell cannot make DNA without it. The notion is that cancer cells being treated with RNAi will die during the course of treatment, with no way to replace them. If you get all the cancer, there is no way for it to "bounce back," and if you miss some, then at least progression has been seriously slowed.

On the point of receptors, that raises an interesting point. The nanoparticles used in this experiment target transferrin receptor, a cell surface receptor for the iron-carrying protein transferrin. Transferrin is highly upregulated in cancer cells because iron is required by many enzymes important to cell division (including ribonucleotide reductase, incidentally). Because it is so vital, cancer cells probably cannot just stop making transferrin. Developing a mutant form of transferrin that the nanoparticles cannot adhere to is a possibility, but there'd be a very narrow window of success (success from the cancer's POV). After all, cancer develops a transferrin receptor because it needs to get iron from transferrin- the same transferrin floating in your bloodstream your healthy cells uses. So whatever stealth transferrin receptor cancer cells come up to hide from nanoparticles still has to be compatible with real transferrin, or the cancer cells will be unable to divide.

Re:Something doesn't add up here.

[Schickeneder]

That was very helpful. Now I have a few more questions.

If the transferrin receptor is the target, how does this make it "cancer-specific"? Is this an abnormal receptor that would not be present in other cells? Or does this approach rely on the target selectively binding to the cancer cells because of the higher concentraiton of these receptors? If that's the case wouldn't we expect to see "collateral" damage (other cells)?

Re:Something doesn't add up here.

[aukset]

There are two parts to this:

1) Get the RNA into the cell in the first place. Anything you want to get into a cell has to pass through the cell membrane, and if the molecule is any larger than H2O, the only way to do that is with a transport mechanism you would find within the cell membrane. In this case, the transferrin receptor that transports Fe from the bloodstream to the interior of the cell.

2) Cause the transcription interference in the DNA itself, as described by the GP. At this point, the transferrin receptor is no longer at issue. While normal cells will definitely uptake the RNA, the idea is that normal cells won't be affected by it because it is designed to interfere only with RRM2, a cancerous mutation.

So...

[vistapwns]

"Smoke 'em if you got 'em?"

Original publication

[DarkPixel]

See paper here http://www.nature.com/nature/journal/vaop/ncurrent/full/nature08956.html and article here http://www.nature.com/news/2010/100321/full/news.2010.138.html

Why do I keep seeing summaries that link to articles that are summaries of summaries of the original publication? Just link to the damn Nature article if that's the source.

Gold nanorods

[Adaeniel]

Gold nanorods have also shown promise for the destruction of cancer cells. The really neat thing about them is that their absorption is tunable based on their size. In turn, they can be tuned to absorb in the near-infrared spectrum. The nanorods are then irradiated with near-infrared radiation, producing heat. This burns away cancer cells locally. There is still debate related to cell death caused by uptake of gold nanorods/nanoparticles.

In summary, we will hopefully be able to pew-pew-pew cancer to death with little damage to other cells. Yes, this whole post is constructed in order to use pew-pew-pew in a science related message.

Re:what if it wins...

[gomiam]

An interesting idea, but it requires developing anti-body targets that make the immune system react. What if it is the immune system that is affected? What if the immune system is so depressed it can react? Adding gene-knockoff RNA helps fight the cancer without relying on third parties. At least, that's what I think the scientists involved decided. Less steps, less risk of failure.

Vitamin D, natural foods, fasting, exercise..

[Paul Fernhout]

Most cancer can be prevented or sometimes cured with the right amount of vitamin D3 (5000 IU daily as a base for most adults with a few exceptions, but you need a blood test periodically to be sure), a diet of mostly organic natural foods (whole grains, fruits, vegetables), occasional fasting, and moderate exercise -- along with quitting smoking and some other lifestyle changes, and living in a cleaner environment (especially clean water), and some positive emotions, spirituality, and community helps too. These things (especially the right amount of vitamin D) will also sometimes prevent or sometimes cure a good amount of the many other chronic diseases of our modern society as well like heart disease, diabetes, depression, -- and maybe even autism which may result in part from inadequate vitamin D by parents before conception, during pregnancy, and while nursing (as dermatologists have told us all to fear the sun and we also live indoors more at screens). For references to all this, see:
Vitamin D:
http://www.vitamindcouncil.org/cancerMain.shtml
http://www.vitamindcouncil.org/treatment.shtml
http://www.vitamindcouncil.org/newsletter/new-harvard-paper-on-autism.shtml
http://www.vitamindcouncil.org/newsletter/2008-october.shtml
http://www.lewrockwell.com/sardi/sardi111.html
Fasting and better diet:
http://www.healthpromoting.com/Articles/articles/PleasureTrap.htm
http://www.amazon.com/Pleasure-Trap-Mastering-Undermines-Happiness/dp/1570671508
http://www.amazon.com/Supernormal-Stimuli-Overran-Evolutionary-Purpose/dp/039306848X
http://books.google.com/books?id=nRurn6C142YC
Lifestyle and cancer:
http://www.huffingtonpost.com/elaine-schattner/we-are-all-fat-and-have-c_b_506247.html
http://online.wsj.com/article/SB10001424052970204251404574342170072865070.html
Exercise:
http://www.letsmove.gov/
Community infrastructure:
http://www.bluezones.com/makeover-about
Positive emotions, community, and spirituality:
http://books.google.com/books?id=RKZreNYKNHQC
http://books.google.com/books?id=bCuC2H-6k_8C

Magic bullets like this RNA-loaded nanoparticle stuff are potentially great (if they have no side effects), but how about just encouraging (and making easy) the simple things first?

We don't have to wait for magic bullets to cure most ill health. Why not put a few trillion US dollars into these things? It would be enormously cost effective. One link above suggests curing vitamin D deficiency alone in Western Europe would save US$4.4 trillion dollars in health care expense over a decade (the USA might see a comparable amount in savings). Of course, in our current economic and sick