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New Nanodevice Can Defeat Resistance to Cancer Drugs, Researchers Claim
Chemotherapy often shrinks tumors at first, but as cancer cells become resistant to drug treatment, the tumors can grow back. A new nanodevice developed by researchers at the Massachusetts Institute of Technology (MIT) may help overcome that by first blocking the gene that confers drug resistance, and then launching a new chemotherapy attack against the disarmed tumors.
The device, which consists of gold nanoparticles embedded in a hydrogel that can be injected or implanted at a tumor site, could also be used more broadly to disrupt any gene involved in cancer, according to the researchers.
“You can target any genetic marker and deliver a drug, including those that don’t necessarily involve drug-resistance pathways. It’s a universal platform for dual therapy,” said senior author Dr. Natalie Artzi. A paper describing the device was published in the Proceedings of the National Academy of Sciences.
To demonstrate the effectiveness of the new approach, Artzi and her colleagues tested it in mice implanted with human triple-negative breast tumors. Such tumors, which lack any of the three most common breast-cancer markers (estrogen receptor, progesterone receptor, and human estrogen receptor 2), are usually difficult to treat. Using the new device to block the gene for multidrug-resistant protein 1 (MRP1) and then delivering the chemotherapy drug 5-fluorouracil, the researchers were able to shrink tumors by 90% in 2 weeks.
MRP1 is one of many genes that can help tumor cells become resistant to chemotherapy. MRP1 codes for a protein that acts as a pump, eliminating cancer drugs from tumor cells and rendering the drugs ineffective. The new pump acts on several drugs other than 5-fluorouracil, including the commonly used cancer drug doxorubicin.
To overcome drug resistance, the researchers created gold nanoparticles coated with strands of DNA complementary to the sequence of MRP1 messenger RNA –– the snippet of genetic material that carries DNA’s instructions to the rest of the cell.
These strands of DNA, which the researchers call “nanobeacons,” fold back on themselves to form a closed hairpin structure. However, when the DNA encounters the correct mRNA sequence inside a cancer cell, it unfolds and binds to the mRNA, preventing it from generating more molecules of the MRP1 protein. As the DNA unfolds, it also releases molecules of 5-fluorouracil that were embedded in the strand. This drug then attacks the tumor cell’s DNA, since MRP1 is no longer around to pump it out of the cell.
When each of these events occurs –– sensing the MRP1 protein and releasing 5-fluorouracil –– the device emits fluorescence of different wavelengths, allowing the researchers to visualize what is happening inside the cells. Because of this, the particles may also be used for diagnosis –– specifically, determining whether a certain cancer-related gene is activated in tumor cells.
The DNA-coated gold nanoparticles are embedded in an adhesive gel that stays in place and coats the tumor after being implanted. This local administration of the particles protects them from the degradation that might occur if they were administered throughout the body, and also enables sustained drug release, the researchers say.
In their mouse studies, they found that the particles could silence MRP1 for up to 2 weeks, with continuous drug release over that period, effectively shrinking tumors.
This approach could be adapted to deliver any kind of drug or gene therapy targeted to a specific gene involved in cancer, the authors say. They are now working on using it to silence a gene that stimulates gastric tumors to metastasize to the lungs.
Source: MIT; March 2, 2015.