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Reducing side effects of chemotherapy with ‘nanoshells’
HOUSTON—One of the biggest drawbacks to chemotherapy, of course, is that it is not very discriminating. While it is toxic to many tumors, it is also highly toxic to healthy cells, and getting it into the body in sufficient amounts to kill cancerous tissues has always been problematic.
However, researchers investigating ways to deliver high doses of cancer-killing drugs inside tumors say that they have demonstrated that using a laser and light-activated gold nanoparticles can effectively and remotely trigger the release of FDA-approved cancer drugs inside cancer cells—something that they have shown in laboratory cultures so far.
The in-vitro study by researchers at Rice University and Northwestern University Feinberg School of Medicine appeared online recently in the Early Edition publication of the Proceedings of the National Academy of Sciences. In the study, researchers used gold nanoshells to deliver toxic doses of the drugs lapatinib and docetaxel inside breast cancer cells. The researchers report that they were able to use a laser to remotely trigger the particles to release the drugs after they entered the cells.
While of course tests “in a dish” are far from showing utility in humans, the work was very much designed with the idea of demonstrating potential clinical utility. As the universities note, “The nanoparticles are nontoxic, the drugs are widely used and the low-power, infrared laser can noninvasively shine through tissue and reach tumors several inches below the skin.”
“In future studies, we plan to use a Trojan-horse strategy to get the drug-laden nanoshells inside tumors,” said Naomi Halas, an engineer, chemist and physicist at Rice University who invented gold nanoshells and has spent more than 15 years researching their anticancer potential. “Macrophages, a type of white blood cell that’s been shown to penetrate tumors, will carry the drug-particle complexes into tumors, and once there we use a laser to release the drugs.”
Co-author Susan Clare, a research associate professor of surgery at the Northwestern University Feinberg School of Medicine, said the PNAS-published study was designed to demonstrate the feasibility of the Trojan-horse approach. In addition to demonstrating that drugs could be released inside cancer cells, the study also showed that in macrophages, the drugs did not detach prior to triggering.
If this approach works in the human body, it would go a long way toward addressing the problem noted at the beginning of this article—if chemo drugs can be delivered directly to the tumors and released locally, side effects and collateral damage to the patient’s body would be greatly reduced.
“Getting chemotherapeutic drugs to penetrate tumors is very challenging,” said Clare, also a Northwestern Medicine breast cancer surgeon. “Drugs tend to get pushed out of tumors rather than drawn in. To get an effective dose at the tumor, patients often have to take so much of the drug that nausea and other side effects become severe. Our hope is that the combination of macrophages and triggered drug-release will boost the effective dose of drugs within tumors so that patients can take less rather than more.”
One of the drugs in the study, lapatinib, is part of a broad class of chemotherapies called tyrosine kinase inhibitors that target specific proteins linked to different types of cancer and, says Amanda Goodman, a Rice alumnus and lead author of the PNAS study: “All the tyrosine kinase inhibitors are notoriously insoluble in water. As a drug class, they have poor bioavailability, which means that a relatively small proportion of the drug in each pill is actually killing cancer cells. If our method works for lapatinib and breast cancer, it may also work for the other drugs in the class.”
Halas invented nanoshells at Rice in the 1990s. About 20 times smaller than a red blood cell, they are made of a sphere of glass covered by a thin layer of gold. Nanoshells can be tuned to capture energy from specific wavelengths of light, including near-infrared, a nonvisible wavelength that passes through most tissues in the body. Clare and Halas’ collaboration on nanoshell-based drug delivery began more than 10 years ago. In earlier work, they showed that a near-IR continuous-wave laser could be used to trigger the release of drugs from nanoshells.
In the latest study, Goodman contrasted the use of continuous-wave laser triggering and triggering with a low-power pulse laser. Using each type of laser, she demonstrated the remotely triggered release of drugs from two types of nanoshell-drug conjugates. One type used a DNA linker and the drug docetaxel, and the other employed a coating of the blood protein albumin to trap and hold lapatinib. In each case, Goodman found she could trigger the release of the drug after the nanoshells were taken up inside cancer cells. She also found no measurable premature release of drugs in macrophages in either case.
Halas and Clare said they hope to begin animal tests of the technology soon and have an established mouse model that could be used for the testing.
This isn’t the first time gold nanoshells and chemo have been combined, though. Back in February 2014, researchers from East China Normal University and Tongji University used gold nanoshells as a building block to which they attached the anticancer drug Doxorubicin and a specific peptide known as A54. Their gold nanoshells had diameters of around 200 nanometers—more than 50 times smaller than a red blood cell. When these nanoshells were tested on human liver cancer cells, the researchers also used nanoshells without the attached peptide. They found that the uptake for nanoshells that had the peptide was threefold that of the uptake seen with the non-peptide nanoshells used as a control.