PICTURE: Imaging results showing a representative set of mice from each group three weeks after treatment. Above left, saline solution. Control. Above right, sole control with artificial enzyme. Bottom left, tagging agent alone …. view More
Researchers led by Katsunori Tanaka and Kenward Vong from the RIKEN Cluster for Pioneering Research (CPR) in Japan have shown that tumor growth can be reduced by a therapy that marks cancer cells with various therapeutic molecules. In one case, the group was able to prevent tumors from forming in mice by targeting cancer cells with a compound that makes it difficult for cells to clump together and form tumors. For pre-existing tumors, they used toxic compounds to target cancer cells, which they destroyed. This study was published in Science Advances on April 23.
One of the major problems with current cancer treatments is that their effects are not limited to cancer cells in the body. The side effects of chemotherapy are well known – hair loss, nausea, exhaustion, weakened immune system and nerve damage. Being able to target cancer cells – and only cancer cells – with therapeutic agents is a dream that is slowly becoming a reality, and the new study from Tanaka’s group at RIKEN CPR is the proof-of-concept. As Tanaka says, “We have succeeded for the first time in treating cancer with metal-catalyzed chemistry in mice.”
The process builds on the group’s previous work using man-made gold-based enzymes – commonly called metalloenzymes – to tag proteins in the body. The marker and the metalloenzyme are both injected into the body, but separately. The metalloenzyme itself is designed to be glycosylated, which means that sugar chains called glycans are attached to its surface. Specific glycans are chosen so that they can bind to target cells in the body. For example, different cancer cells can be identified by the unique types of lectins – glycan-binding proteins – that are embedded in their outer membranes. For this experiment, the researchers built a glycosylated metalloenzyme that could attach itself to the specific lectins on the outside of HeLa cancer cells and thus target them. After the labeling agent has reacted with the metalloenzyme, it can perform the desired function and label the protein of interest on the cancer cell. Only cancer cells targeted by the glycated metalloenzyme can be tagged in this way.
The team conducted two key targeted drug delivery tests. The first test used a form of RGD that became functional after reacting with the artificial enzyme attached to the target cancer cell. RGD was chosen because previous tests indicated that it interfered with the ability of cancer cells to clump together and form tumors. They injected HeLa cancer cells into mice and then injected them with both the glycated metalloenzyme and RGD. Control mice were injected with the artificial enzyme alone, RGD alone, or saline. The mice were monitored for 81 days. While all controls developed tumors and died long before day 81, the mice treated with selective cell therapy with RGD tagging had a survival rate of 40%. The imaging analysis showed that the treatment disrupted the tumor’s incidence and progression.
The second test is designed to target tumors that have already formed. To do this, the team used the same glycated metalloenzyme, but with a form of non-toxic doxorubicin that became functional after reacting with the metalloenzyme. Previous tests showed the drug was harmless until it interacted with the metalloenzyme and at that point released toxic doxorubicin. In this way, only targeted cancer cells were affected by the drug. Testing in mice was similar to testing with RGD, except that tumors were allowed to develop for a week before the artificial enzyme and marker were injected. Mice given the real treatment showed reduced tumor growth and a higher survival rate over 77 days.
“We were able to use our system to deliver metalloenzymes to cancer cells in living mice that reacted with tracers to provide targeted drug therapies that reduced the incidence and growth of tumors,” says Tanaka. “The next step is certainly clinical application in humans.”
Vong et al. (2021) Disruption of tumor onset and growth by selective cell labeling therapy (SeCT). Sci Adv. Doi: 10.1126 / sciadv.abg4038.
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