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Next Generation: In Vivo Drug Factories

Researchers use UV light to stimulate protein production in nano-sized delivery capsules in mice.

By | August 13, 2012

image: Next Generation: In Vivo Drug Factories Nanoparticles expressing a GFP reporter. Avi Schroeder

Device: Science is one step closer to producing drugs in the right place at the right time in the body, avoiding the collateral damage of untargeted treatments. Researchers led by Daniel Anderson at the Massachusetts Institute of Technology have designed nanoparticles that can be stimulated via UV light to produce proteins on demand in vivo.

The new method, which involves packaging the molecular machinery for making proteins into a membraned capsule, allows the researchers to spatially and temporally regulate protein production, said Zhen Gu, who also researches nanoparticle drug delivery at North Carolina State and University of North Carolina, Chapel Hill, but did not participate in the research. “They can control generation of a protein at any time with a trigger of light.”

The scientists created the nano-sized “protein factories” by using lipids to encapsulate polymerase and other machinery necessary for protein production from E. coli, along with a DNA plasmid containing a gene of interest. To block transcription until the right moment, they added a DNA “photo-labile cage” to the plasmid—a small chemical that inhibits transcription but is cleaved by exposure to UV light.

To test the principle in vivo, the researchers used luciferase as the reporter protein and injected mice with the nanovesicles. After zapping them with UV light at the site of injection, they were able to measure a local burst of luminescence.

What’s new: Protein expression in liposomes has been possible for at least 10 years, said Mitchel Doktycz, a synthetic biologist at Oak Ridge National Laboratory in Tennessee. What is new, said Doktycz, who did not participate in the research, is being able to control the timing of protein expression in an animal. “They can do it remotely,” he said.

And that switch is not limited to UV light, added Gu, but will likely work with other wavelengths using different chemical ligands.

 

Close-up of a GFP-positive nanoparticle.
Close-up of a GFP-positive nanoparticle.
Credit: Avi Schroeder

 

Importance: Many life-saving drugs, such as chemotherapy, can have nasty and toxic effects outside the tissues they’re designed to treat. The goal of remotely-controlled factories like Anderson’s is to produce a drug in a specific place (such as a tumor) at a specific time (after enough particles have accumulated to produce a therapeutic effect). Anderson’s group is “trying to deliver a payload, [and] activate [it] in a specific spot, so they’re not dosing everywhere,” Doktycz explained—which has the potential to minimize side effects while maximizing therapeutic benefit.

Needs improvement: “We have a long way to go still before we have a drug factory that will land in a target tissue to produce a drug of interest,” noted Anderson. The study has proved the principle of the first step—getting the protein expressed on signal—but future research will need to ensure that the nanoparticles and the proteins they produce aren’t toxic in the wrong place, and that they get to the right location. Targeting the nanoparticles to the appropriate tissues might be achieved by “decorating” the surface of the vesicles with specific proteins, said Gu.

Furthermore, although most of the materials in the current particles are probably safe, some are microorganism-derived, Anderson pointed out, and most likely need to be switched to human alternatives. Finally, getting the drug expressed is also just one part of the problem, said Doktycz. So far the system has no way to re-cage the DNA to halt protein production when it’s no longer needed. “Turning on is one thing, but turning off is another,” he said.

A. Schroeder et al., “Remotely activated protein-producing nanoparticles,” Nano Letters, 12:2685-89, 2012.

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Comments

Avatar of: Edo McGowan

Edo McGowan

Posts: 2

August 13, 2012

Will be interesting to see how this will get distributed to tissues with damaged or poor perfusion, a problem now facing many drugs.

Avatar of: Nadya Gytkovitch

Nadya Gytkovitch

Posts: 1457

August 14, 2012

I think it's just a matter of dose and kinetics. Maybe intraarterial injection localized near the damaged area would be helpful.

Avatar of: Nadya Gytkovitch

Nadya Gytkovitch

Posts: 1457

August 14, 2012

How long is a lifetime of the
polymerase and other machinery necessary for protein production from E. coli ? Maybe not need to turn off the production of the protein, it will decay naturally. And another question -
if it "will likely work with other wavelengths using different chemical ligands", does it mean that patient should be kept away from any visible light up to full inactivation of the medicine?

Avatar of: Jessica Goldfeld-Katz

Jessica Goldfeld-Katz

Posts: 1457

August 14, 2012

I hope the scientists will succeed and that a much more "targeted" and safer drug administration system will be available.

Avatar of: Bebe Johnson

Bebe Johnson

Posts: 1457

August 17, 2012

A few ideas
Ways to inhibit:
- You can protect the non-target areas by surrounding the target area with heavy water (deuterium) or inject lipid-philic molecules into the target area first to keep the capsules in the target area. OR before injection biological walls can be built using myosin and actin then treated.
- Or the capsule can degenerate, become apoptic after a certain amount of time which will encourage white blood cells and lysosomes to clean the area.
- And gene expression can be controlled using pH, heat, inhibitors or a stop sequence.
GOOD LUCK !

Avatar of: Su Lei

Su Lei

Posts: 1

August 19, 2012

To turn off the protein, I think we can take advantage of light activated proteins, like LOV. Try to engineer the protein that is functional or stable only when the UV light is presented. So within the tumor, the UV is on, protein start to synthesis, and the protein is functional/stable, outside of the tumor, no UV and protein is dis-functional/degraded. HA! what do you think?

Avatar of: Lobo Mexicano

Lobo Mexicano

Posts: 1

August 28, 2012

targeting is the key!

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