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February 9, 2018

New Method Overcomes Cancer Cells’ Multidrug Resistance

  • Scientists have developed a novel technique that uses specially designed nanoparticles and near-infrared (NIR) laser treatment to cause cancer cells to lose their multidrug resistance capabilities for days at a time. This creates a therapeutic window for chemotherapy to combat even the most drug-resistant cells left behind after surgery or earlier treatment, according to the researchers.

    The group's findings (“Targeted Production of Reactive Oxygen Species in Mitochondria to Overcome Cancer Drug Resistance”) were published in Nature Communications.

    “The multidrug resistance phenotype is associated with the overexpression of the adenosine triphosphate (ATP)-driven transmembrane efflux pumps in cancer cells. Here, we report a lipid membrane-coated silica-carbon (LSC) hybrid nanoparticle that targets mitochondria through pyruvate, to specifically produce reactive oxygen species (ROS) in mitochondria under near-infrared (NIR) laser irradiation. The ROS can oxidize the NADH into NAD+ to reduce the amount of ATP available for the efflux pumps. The treatment with LSC nanoparticles and NIR laser irradiation also reduces the expression and increases the intracellular distribution of the efflux pumps,” write the investigators.

    “Consequently, multidrug-resistant cancer cells lose their multidrug resistance capability for at least 5 days, creating a therapeutic window for chemotherapy. Our in vivo data show that the drug-laden LSC nanoparticles in combination with NIR laser treatment can effectively inhibit the growth of multidrug-resistant tumors with no evident systemic toxicity.”

    "By administering chemotherapy within this 'therapeutic window,' oncologists could apply a lower dose of chemotherapy drugs to patients, with the potential for an improved treatment outcome—all while minimizing drug toxicity to healthy organs," said Xiaoming "Shawn" He, Ph.D., University of Maryland Fischell Department of Bioengineering Professor.

    One of the primary reasons cancer cells develop resistance is the overexpression of efflux pumps, proteins that protect a cell by pumping out unwanted toxic substances before they can reach their intended target. In the same way that efflux pumps work hard to protect against toxins, they also expel virtually all clinically relevant chemotherapy drugs.

    Fortunately, notes Dr. He, efflux pumps require a source of chemical energy to perform their function. As such, by cutting off the energy supply to the efflux pumps, oncologists could lower—or even eliminate—a cell's resistance to drugs, such as those administered for chemotherapy. 

    Recognizing this, Dr. He and his research team developed a way to reduce the amount of chemical energy (ATP) available to the efflux pumps in cancer cells.

    The team, which also included researchers from Ohio State University, University of Virginia, University of Missouri School of Medicine, Shanghai University of Traditional Chinese Medicine, and Indiana University School of Medicine, targeted a specially designed nanoparticle to the mitochondrion. Once the nanoparticles reach the cancer cells' mitochondria, the researchers apply NIR laser treatment to trigger a chemical reaction that reduces the amount of ATP available to the pumps and, thus, cuts off their power supply. Such treatment both reduces the expression of the efflux pumps and decreases their distribution on the cell plasma membrane.

    The research team's findings demonstrate that the drug-laden nanoparticles—in combination with NIR laser treatment—can effectively inhibit the growth of multidrug-resistant tumors with no evident systemic toxicity. 

    "For years, researchers have focused on delivering more chemotherapy drugs into cancer cells using nanoparticles, without targeting the root of drug resistance," Dr. He said. "This meant that the cancer cells maintained their ability to expel the chemotherapy drugs, which limited any enhancement of the cancer therapy. 

    “To address this challenge, our research group is using nanoparticles not only to deliver more chemotherapy drugs to the target site within cancer cells, but also to compromise the function of the efflux pumps and thereby significantly improve safety and efficacy of cancer therapy."

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