Curbing chemoresistant nanoparticles significantly prolongs survival

Recently, scientists at the University of Pittsburgh have deciphered the mechanism by which cancer cells resist chemotherapy and the key protein Xkr8 in it, and have developed an anti-cancer nanoparticle that can deliver Xkr8-targeted drugs and chemotherapy drugs simultaneously to tumors. The tumors in mice receiving this combined treatment regimen were significantly smaller in size, which survived longer than those receiving only one treatment. These results were recently published in the prestigious academic journal Nature Nanotechnology.

Chemotherapy has been the mainstream therapy for cancer treatment for decades, extending the life span of countless patients. However, its shortcomings are also obvious—chemotherapy drugs are poorly selective and can damage normal tissue cells while killing cancer cells, which then leads to a series of toxic side effects, so doctors must strike a balance between killing cancer cells and harming healthy cells when using the drugs. Cancer cells that survive chemotherapy often develop resistance to the drug, resulting in a significant reduction in the effectiveness of the patient's subsequent chemotherapy. As the article's corresponding author, Dr. Song Li, "Chemotherapy can kill tumor cells, but it has limitations, and there are many ways for tumor cells to survive."

The mechanism behind cancer chemoresistance focuses on phosphatidylserine (PS), a phospholipid molecule prevalent in cells, usually located in the inner layer of the cell membrane. PS in healthy cells is involved in the apoptotic process, and when PS inside a cell moves to the outside, that cell is marked for "destruction" by the immune system. When cancer cells are exposed to chemotherapeutic drugs, this process is abnormal. The cancer cells move the PS to the surface of the cell, but instead of being marked as "destroyed", the PS outgrowth keeps the immune system from destroying them. In this case, even though most of the cancer cells are destroyed by the chemotherapy drugs, the surviving cancer cells eventually cause the cancer to recur. How to block the transfer of PS from the inside of the cell membrane to the outside becomes the key to overcoming cancer drug resistance.

Previously, researchers have tried to develop antibodies against PS, and some therapeutic combinations of PS inhibitor drugs with other therapies have moved into clinical studies, but because PS is involved in important physiological processes in healthy cells, such treatments carry the risk of serious side effects. In this study, the researchers took an alternative approach—instead of inhibiting PS activity, they wanted to prevent PS from being exposed to the outside from inside the cell. To do this, the team looked to the Xkr8 protein, a molecule that regulates the movement of PS from the interior to the surface of cells.

In this study, when the researchers treated the cancer cell lines with common chemotherapeutic drugs, the levels of Xkr8 increased dramatically, a phenomenon that inspired them—if the production of Xkr8 was blocked simultaneously with chemotherapy, it might be possible to prevent cancer cells from becoming resistant to chemotherapy. The researchers eventually chose to combine siRNA and chemotherapy drugs and delivered both drugs to the body using nanoparticles (

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