Viral Capsids: Nature's Nanoengineers
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A virus, essentially nucleic acid clothed in a protein coat (also called capsid), is designed for its lifestyle as a cellular parasite. Targeting, packaging and delivery have all been optimized over billions of years of evolution. To search out target cells, the viral coat incorporates recognition and docking sites for specific cell types. To stabilize its negatively charged genetic package, a virus may carry a remarkably high positive charge on the capsid interior. And once it arrives at its destination, a virus delivers its genes into the interior of the targeted cell, where it usurps cellular machinery for viral purposes. Now researchers are taking advantage of these viral systems to develop clever nanotechnology applications in medical imaging and drug delivery, as well as new approaches to building electronic devices.
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Mark Young and Trevor Douglas of Montana State University, spent several years sleuthing the structure and assembly of viruses. They focused on the well-studied Cowpea Chlorotic Mottle Virus (CCMV). The viral coat of CCMV is composed of identical protein subunits that self-assemble into a quasispherical shape known as an icosahedron. This geometry forms the largest volume of a given size that can be constituted from identical subunits, notes Young. The subunits are organized into five-sided and six-sided capsomeres, which are arranged to form a pattern similar to that on a soccer ball. CCMV has gated pores that open and close according to the chemistry of its surrounding environment.
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Armed with an arsenal of CCMV knowledge, the researchers began to explore whether they could redesign the capsid to both incorporate an imaging agent and zoom in on new targets. In addition, they wondered, what could be packaged inside the viral capsid in place of nuclei acid? And how could the gates be triggered to make deliveries? It turns out that the capsid, assembled without its nucleic acid and thus no longer infectious, can serve as a highly modifiable and versatile addition to the nanoengineer"s toolbox. Conveniently, the empty capsid even self-assembles in the test tube or in yeast cells genetically engineered to produce subunits.
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To conquer a metastasized cancer, physicians must identify the sites of new tumours and then selectively kill the wayward cells. CCMV capsids can potentially be engineered to achieve both goals. For example, CCMV capsids could improve detection of tiny new tumours by magnetic resonance imaging (MRI). MRI identifies the differing responses of hydrogen atoms of water to the presence of a powerful magnetic field. Prior to being scanned, the patient may receive an injection of an imaging agent, most commonly gadolinium. The agent as currently given, makes areas of interest more distinct but usually cannot resolve extremely small metastases. Over the past two years, Young, Douglas and their colleagues significantly raised contrast levels in MRI images by incorporating the gadolinium atoms into CCMV protein shells. This promotes gadolinium"s interaction with water molecules. That"s because the gadolinium molecules tend to be in higher concentration at any given location. Also, unlike today"s gadolinium agent, which tends to clump, the gadolinium bound to the capsid surface keeps the atoms evenly distributed and available to interact with water.\
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To attach gadolinium to the capsids, the scientists exchanged the agent for the usual calcium--normally, during capsid assembly, calcium binds to the protein shell at sites between the subunits. To further knit gadolinium to the capsid, the researchers genetically engineered changes on the viral genome that optimized the binding sites for gadolinium. Now that they had an improved imaging agent, the scientists wanted to specifically light up metastases in the MRI images. To do this, the investigators placed protein-based docking molecules on the capsids. These docking sites would bind with proteins expressed on the surface of cancer cells, so the gadolinium-bound capsids would collect at tumour sites.
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Again, the investigators turned to genetic engineering, making changes in the viral genome. In fact, they found that different types of docking sites could be placed on one capsid, potentially making it possible to search for several cancer types simultaneously. By combining docking sites and gadolinium onto each capsid, the investigators could cluster the capsids around tiny clumps of cancer cells and image them in experimental systems. But what about eradicating the metastasized cancer?
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Bereft of its nucleic acid, the viral capsid could be a handy suitcase for transporting potent anticancer compounds to tumour sites. Over the past four years, the researchers have shown that a variety of compounds can be placed inside the capsule. They showed that some therapeutic agents used to treat cancer can be encapsulated through the viral gates or, in a few cases, can actually be manufactured in situ using the capsid as a tiny reaction vessel. That left a final puzzle: Once docked at the tumour with the drugs, how would the capsid deliver its toxic package? The viral gate with which nature has endowed CCMV is controlled by pH, which isn"t a useful trigger for delivering medication to specific sites.
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Again, the scientists reengineered the evolutionary solution and designed gates controlled by redox potential (the oxidation state of a local environment, which influences the tendency of a molecule to lose or gain an electron). For initial work, the scientists have used CCMV, which, as a plant virus, does not enter human cells; however, the final delivery vehicle could be a reconfigured human virus that does slip into human cells. Since interiors of human cells have higher redox potential than the bloodstream, viral capsids could be shut tight in transit but will open their redox-controlled gates once they enter targeted cancer cells. The scientists are also developing another type of gate that is triggered by a type of radiation commonly used in cancer therapy. The team is currently exploring how the modified virus capsules work in a mouse model system and is encouraged by promising initial results.
