• Paula Hammond, Bayer Professor of Chemical Engineering and a member of the David H. Koch Institute for Integrative Cancer Research at MIT.

    Photo: Dominick Reuter

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  • The outer layer of this nanoparticle (in yellow) falls off in an acidic environment.

    Image: Stephen Morton

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Removable ‘cloak’ for nanoparticles helps them target tumors

New MIT particles could be used to deliver cancer drugs to nearly any type of tumor.


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MIT chemical engineers have designed a new type of drug-delivery nanoparticle that exploits a trait shared by almost all tumors: They are more acidic than healthy tissues.

Such particles could target nearly any type of tumor, and can be designed to carry virtually any type of drug, says Paula Hammond, a member of the David H. Koch Institute for Integrative Cancer Research at MIT and senior author of a paper describing the particles in the journal ACS Nano.

Like most other drug-delivering nanoparticles, the new MIT particles are cloaked in a polymer layer that protects them from being degraded by the bloodstream. However, the MIT team, including lead author and postdoctoral associate Zhiyong Poon, designed this outer layer to fall off after entering the slightly more acidic environment near a tumor. That reveals another layer that is able to penetrate individual tumor cells.

In the ACS Nano paper, which went online April 23, the researchers reported that, in mice, their particles can survive in the bloodstream for up to 24 hours, accumulate at tumor sites and enter tumor cells.

A new target

The new MIT approach differs from that taken by most nanoparticle designers. Typically, researchers try to target their particles to a tumor by decorating them with molecules that bind specifically to proteins found on the surface of cancer cells. The problem with that strategy is that it’s difficult to find the right target — a molecule found on all of the cancer cells in a particular tumor, but not on healthy cells. Also, a target that works for one type of cancer might not work for another.

Hammond and her colleagues decided to take advantage of tumor acidity, which is a byproduct of its revved-up metabolism. Tumor cells grow and divide much more rapidly than normal cells, and that metabolic activity uses up a lot of oxygen, which increases acidity. As the tumor grows, the tissue becomes more and more acidic.

To build their targeted particles, the researchers used a technique called “layer-by-layer assembly.” This means each layer can be tailored to perform a specific function.

When the outer layer (made of polyethylene glycol, or PEG) breaks down in the tumor’s acidic environment, a positively charged middle layer is revealed. That positive charge helps to overcome another obstacle to nanoparticle drug delivery: Once the particles reach a tumor, it’s difficult to get them to enter the cells. Particles with a positive charge can penetrate the negatively charged cell membrane, but such particles can’t be injected into the body without a “cloak” of some kind because they would also destroy healthy tissues.


The polymer coating (light blue) is shed as the particle approaches a tumor, exposing positive charges. Those charges help the particle be absorbed through the tumor cell membrane.
Image: Stephen Morton

The nanoparticles’ innermost layer can be a polymer that carries a cancer drug, or a quantum dot that could be used for imaging, or virtually anything else that the designer might want to deliver, says Hammond, who is the Bayer Professor of Chemical Engineering at MIT.

Layer by layer

Other researchers have tried to design nanoparticles that take advantage of tumors’ acidity, but Hammond’s particles are the first that have been successfully tested in living animals.

Jinming Gao, professor of oncology and pharmacology at the University of Texas Southwestern Medical Center, says it is “quite clever” to use layer-by-layer assembly to create particles with a protective layer that can be shed when the particles reach their targets. “It is a nice proof of concept,” says Gao, who was not part of the research team. “This could serve as a general strategy to target acidic tumor microenvironment for improved drug delivery.”

The researchers are planning to further develop these particles and test their ability to deliver drugs in animals. Hammond says she expects it could take five to 10 years of development before human clinical trials could begin.

Hammond’s team is also working on nanoparticles that can carry multiple payloads. For example, the outer PEG layer might carry a drug or a gene that would “prime” the tumor cells to be susceptible to another drug carried in the particle’s core.


Topics: Cancer, Chemistry and chemical engineering, Koch Institute, Nanoparticles, Nanoscience and nanotechnology

Comments

Something that the Cancer Cells have but not others... A great exploitation of the differences, and also might be helpful for various types of tumors... It looks like there will always be some difference between normal and illconditioned cells.. The acid level difference due to oxygen consumption... But as the cells gets less and less, acidicity might degrade... ;)However, this technique would cure many tumors, or bring many tumors to a curable point with existing techniques... Which tells us further push for the differences between the normal cells and cancers cells need to be found... Else If, a cell by cell cleaning through imaging techniques which requires further imaging techniques, those not leading to illnesses through their long periods of usage...
Binding nano particles with surface proteins was basically done for forming clusters of nano-particles for concentrating heat delivered from outside. Whereas here the aim is to place the nano-particle inside the cancer cell ( for drug delivery ). In addition the chances of selective binding of NP's with protein are not that bad. (specially with specific targeting with secondary NP ). As both the approaches differs in their Aim , they should not be compared for finding advantages.
Perhaps an immune stimulating protein that would evoke an immune response could be added to the nanoparticle. It would be unmasked in the acid environment of the tumor when the PEG layer falls off, and then the nanoparticle could stick to the nearest cells because a sticky region on the nanoparticle would also be unveiled. The cancer cells would now be decorated with a protein that would evoke an immune response against them. This might stimulate an immune response against the cancer that would kill most of the cancer cells.
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