Nanoparticle Factories Churn Out Proteins - Could Manufacture Cancer Drugs at Tumor Sites
Drugs made of protein have shown promise in treating cancer, but they are difficult to deliver because the body usually breaks down proteins before they reach their destination. To get around that obstacle, a team of researchers from the MIT–Harvard Center for Cancer Nanotechnology Excellence (MIT–Harvard CCNE) has developed a new type of nanoparticle that can synthesize proteins on demand. Once these "protein–factory" particles reach their targets, the researchers can turn on protein synthesis by shining ultraviolet light on them.
The particles, say the investigators, could be used to deliver small proteins that kill cancer cells, and eventually larger proteins such as antibodies that trigger the immune system to destroy tumors. This work represents the first proof of concept that it is possible to synthesize new compounds from inert starting materials inside the body. The MIT–Harvard CCNE team, led by Robert Langer and member Daniel Anderson, published the details of this system in the journal NanoLetters.
The researchers came up with the idea for protein–building particles when trying to think of new ways to attack metastatic tumors—those that spread from the original cancer site to other parts of the body. Such metastases cause 90 percent of cancer deaths. They decided to mimic the protein–manufacturing strategy found in nature. Cells store their protein–building instructions in DNA, which is then copied into messenger RNA (mRNA). That mRNA carries protein blueprints to cell structures called ribosomes, which read the mRNA and translate it into amino acid sequences. Amino acids are strung together to form proteins.
The researchers designed the new nanoparticles to self–assemble from a mixture that includes lipids—which form the particles' outer shells—plus a mixture of ribosomes, amino acids, and the enzymes needed for protein synthesis. Also included in the mixture are DNA sequences for the desired proteins. The DNA is trapped by a chemical compound called DMNPE, which reversibly binds to it. This compound releases the DNA when exposed to ultraviolet light, giving the investigators the ability to turn on protein production at their command.
In this study, particles were programmed to produce either green fluorescent protein (GFP) or luciferase, both of which are easily detected. Tests in mice showed that the particles were successfully prompted to produce protein when irradiated with UV light.
Waiting until the particles reach their destination before activating them could help prevent side effects from a particularly toxic drug. However, more testing must be done to demonstrate that the particles would reach their intended destination in humans, and that they can be used to produce therapeutic proteins. Indeed, the MIT–Harvard CCNE team is now developing nanoparticles that can synthesize potential cancer drugs. Some of these proteins are toxic to both cancerous and healthy cells, it may be possible using this system to turn on protein production only in the tumor, avoiding side effects in healthy cells.
The team is also working on new ways to activate the nanoparticles. Possible approaches include production triggered by acidity level or other biological conditions specific to certain body regions or cells.
This work, which is detailed in a paper titled, "Remotely–activated protein–producing nanoparticles," was supported in part by the NCI Alliance for Nanotechnology in Cancer, a comprehensive initiative designed to accelerate the application of nanotechnology to the prevention, diagnosis, and treatment of cancer. An abstract of this paper is available at the journal's website.