A team of researchers writing in the journal applied Chemistry has developed a bioorthogonal molecular system for the targeted introduction of nitrate ions into cells. Their system releases nitrate ions into cancer cells using a “click-to-release” strategy, and these ions, along with other agents, help induce cell death. The system could improve the synergistic effects of different cancer therapeutics.
Cells rapidly convert nitrate ions into nitric oxide (NO), which is involved in many cellular processes. For example, it can enhance the effects of various cancer drugs by forming reactive oxygen species. However, the targeted introduction of nitrite to a specific location is complicated.
The research groups of Fude Feng from Nanjing University and Shu Wang from the Chinese Academy of Sciences, Beijing, China, have now developed a bioorthogonal system that transports nitrate ions together with other active substances to the endoplasmic reticulum and releases them there.
Bioorthogonal systems enable useful chemical reactions (“click reactions”) in cells without the reaction partners having any negative effects on the body on their way to the target site. They have paved the way for an exciting array of novel treatment approaches. Evidence of this is the fact that the 2022 Nobel Prize in Chemistry was awarded for the development of click chemistry and bioorthogonal chemistry.
In order to transport reaction partners to a target site without them taking part in undesired reactions, nitrate ions must be bound to a carrier molecule as a nitro group. However, the conditions required to release nitrite again when it reaches its destination are usually much harsher than in living cells. For this reason, the researchers designed two bioorthogonal precursors: one for the delivery of the nitro group and other drugs, and another for the click-to-release reaction by reacting with the first precursor.
The first of the two progenitors, ER-Non, played a number of roles. First, it is readily taken up by the endoplasmic reticulum. Not only do many important cell processes take place in this cell organelle, it is also the site of action of numerous drugs. Secondly, in addition to the nitro group, ER-Non transported the active substance novidamid, which triggers cellular stress reactions at high doses and can thus induce cancer cells to initiate cell death.
The other molecular precursor, a dithiol, is activated by enzymes typical of cancer cells. In a click-to-release reaction, the activated molecule releases both the nitrite and novidamide from ER-Non. The chemicals are not simply released; the reaction causes the new substance to fluoresce and thus becomes a photosensitizer.
Upon exposure to light, it enhances the ability of nitrite ion and novidamide to generate reactive oxygen species and thereby induce cellular stress. This phenomenon of photosensitization is used in photodynamic cancer therapy.
The researchers tested their bioorthogonal system on liver cancer cells and observed inhibited growth of these cells. They also observed a remarkable increase in reactive oxygen species upon addition of both bioorthogonal components. Since neither component alone would exert this effect, the team concluded that synergistic effects are occurring. This opens up new possibilities for more effective cancer therapies.
Jian Sun et al., Dithiol‐activated bioorthogonal chemistry for endoplasmic reticulum‐directed synergistic chemophototherapy, International edition of Angewandte Chemie (2022). DOI: 10.1002/anie.202213765
Quote: Bioorthogonal Introduction of Nitrite Ions into Cells for Cancer Therapy (2022, November 25), retrieved November 25, 2022 from https://phys.org/news/2022-11-bioorthogonal-introduction-nitrite-ions-cells. html
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