Removable "Cloak" Designed for Nanoparticles to Target Tumors

Chemical engineers have designed a new type of drug-delivery nanoparticle that exploits a trait shared by nearly 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, according to Dr. Paula Hammond, a member of the David H. Koch Institute for Integrative Cancer Research at the Massachusetts Institute of Technology (MIT; Cambridge, MA, USA) and senior author of an article describing the particles online April 23, 2011, in the journal ACS Nano.

Similar to 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 Dr. 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 article, the researchers reported that, in mice, their particles survive in the bloodstream for up to 24 hours, accumulate at tumor sites and enter tumor cells. 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 difficulty with that approach is that it is difficult to find the right target--a molecule found on all of the cancer cells in a particular tumor, but not on healthy cells. In addition, a target that works for one type of cancer might not work for another.

Dr. Hammond and her colleagues decided to exploit the properties of tumor acidity, which is a byproduct of its increased 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 construct their targeted particles, the researchers used a technique called "layer-by-layer assembly." This means each layer can be customized to perform a specific function.

When the outer layer (comprised of polyethylene glycol [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 is difficult to get them to enter the cells. Particles with a positive charge can penetrate the negatively charged cell membrane, but such particles cannot be injected into the body without a "cloak" of some kind because they would also destroy healthy tissues.

The polymer coating is shed as the particle approaches a tumor, exposing positive charges. Those charges help the particle be absorbed through the tumor cell membrane. 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, according to Dr. Hammond, who is a professor of chemical engineering at MIT.

Other researchers have tried to design nanoparticles that take advantage of tumors' acidity, but Dr. Hammond's particles are the first that have been successfully tested in living animals. The researchers are planning to additionally develop these particles and assess their ability to deliver drugs in lab animals. Dr. Hammond expects it could take five to 10 years of development before human clinical trials could begin.

Dr. 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.

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