Cancer therapy using on-site synthesis of anticancer drugs

Date:
January 10, 2022
Source:
RIKEN
Summary:
Researchers have successfully treated cancer in mice using
metal catalysts that assemble anticancer drugs together inside
the body. This study is the first report of therapeutic in vivo
synthetic chemistry being used to make anticancer substances where
they are needed simply by injecting their ingredients through a
vein. Because this technique avoids indiscriminate tissue damage,
it is expected to have a significant impact on cancer treatment.



FULL STORY ==========================================================================
An international research group at the RIKEN Cluster for Pioneering
Research (CPR) has successfully treated cancer in mice using
metal catalysts that assemble anticancer drugs together inside the
body. Published in the scientific journal Nature Communications, the
study is the first report of therapeutic in vivo synthetic chemistry
being used to make anticancer substances where they are needed simply
by injecting their ingredients through a vein. Because this technique
avoids indiscriminate tissue damage, it is expected to have a significant impact on cancer treatment.


========================================================================== Aside from effectiveness at killing cancer cells, a major challenge
to cancer chemotherapy is how to mitigate the toxic side effects on
the body. Drugs that can damage cancer cells can damage non-cancerous
cells as well, and the negative side effects of chemotherapy can cause permanent and debilitating damage. Current methods for reducing these
side effects include selective delivery of anticancer drugs to cancer
tissue (drug delivery) and conversion of non-toxic compounds (prodrugs)
into toxic compounds nearby the cancerous tissue.

Katsunori Tanaka at RIKEN CPR, who led the new study, has developed
a method for activating prodrugs using transition-metal catalysis
inside the body. When the catalyst is injected into an organism, it
usually has no effect because it is destroyed by antioxidants such as glutathione. By placing the transition- metal catalysts inside special
pockets within a protein, Tanaka and his colleagues have been able
to avoid this problem and stabilize the catalytic function in vivo,
thus ensuring that the chemical reaction can proceed efficiently in the
body. For this technique to work, the catalyst needs to selectively find
its way to the cancer. As in their previous studies, the team targeted
the catalyst to the cancer by attaching chains of cancer-binding sugar molecules to the surface of the carrier protein. Using these techniques, Tanaka's group succeeded in inhibiting cancer growth and metastasis, as
well as reducing the side effects. The new study is a proof of concept
in which cancer in mice was treated by actually assembling anticancer
drugs inside the body near the cancer cells. "In the past, we used
similar methods to attach anticancer drugs to tumors," says Tanaka,
"but here, we were able to avoid putting any toxic drugs into the
body at all." Noting that the basic skeleton of most anticancer drugs
contains a benzene ring, the researchers started by making benzene rings
inside the body using transition-metal catalysts. "No one believed that artificially synthesizing benzene rings inside the body was possible, but
I was confident that we could do it based on our previous achievements,"
says Tanaka. Using a transition metal-catalyzed complex designed for
selective delivery to cancerous tissues, they succeeded in efficiently
creating the benzene-rings needed by cancer drugs in the vicinity of
cancer cells. By using non-toxic substances, and only joining them
together to form active anticancer drugs at the tumor site, they saw a 1000-times increase in the cancer-inhibiting activity of the drugs.

Simply administering the ingredients needed for the drug, along with the transition-metal catalyst, through a vein, cancer growth was inhibited
without side effects such as weight loss.

This is the first time that active anticancer drugs have been assembled
on-site and effectively combatted cancer by simply injecting the
ingredients for the drug through a vein. In addition to benzene, the methodology developed in this study is expected to enable a variety of
other molecules to be synthesized inside the body. The hope is that this
type of chemotherapy will become a useful therapeutic platform for the
future of cancer treatment.

"Many patients with cancer are dying because of the side effects of
treatment.

We believe our technology, which attacks cancer cells highly
effectively without side effects, will be able to save lives,"
says Tanaka. "The method will also allow us to reconsider using
compounds that have not been used before because they were too
toxic when delivered to the whole body. Now they can be synthesized
at the tumor site without affecting healthy tissue. We believe
this is a paradigm shift for pharmaceuticals and drug discovery." ========================================================================== Story Source: Materials provided by RIKEN. Note: Content may be edited
for style and length.


========================================================================== Journal Reference:
1. Igor Nasibullin, Ivan Smirnov, Peni Ahmadi, Kenward Vong, Almira
Kurbangalieva, Katsunori Tanaka. Synthetic prodrug design enables
biocatalytic activation in mice to elicit tumor growth suppression.

Nature Communications, 2022; 13 (1) DOI: 10.1038/s41467-021-27804-5 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/01/220110103243.htm
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