Microwave oven for cancer
Nanoparticles activate STING in "cold" tumors
Peter Kazimirov, PCR.news
The stimulator of an interferon gene (STING) plays an important role in the formation of an immune response. Activation of STING ultimately leads to the expression of type I interferon and other cytokines. STING activators, such as cyclic diadenosine monophosphate (CDA), obtained from bacterial cultures, have a high therapeutic potential in the treatment of cancer. However, such compounds are extremely unstable and quickly disintegrate after introduction into the body, and existing delivery methods are ineffective. An international team of scientists has presented a new type of nanoparticles for effective delivery of CDA to cancer tissues.
These nanoparticles consist of a hydrophilic core of non-toxic zinc phosphate surrounded by a double lipid membrane. The particles are capable of carrying both hydrophilic and hydrophobic substances and can be "programmed" to release the contents when a certain stimulus is received. In this paper, scientists presented nanoparticles carrying CDA — ZnCDA.
The ability of ZnCDA to activate STING signaling pathways was tested on a culture of STING reporter cells. In vivo, therapeutic efficacy testing was carried out on two mouse models — adenocarcinoma and liver metastases. Five out of five mice with adenocarcinoma and five out of seven mice with liver metastases showed complete cancer elimination after ZnCDA therapy. The scientists also compared the effectiveness of ZnCDA with the currently most common method of delivery of CDA — liposomes. Liposomal delivery increased the half-life of CDA in vivo from 0.21 to 3.30 hours, while ZnCDA allowed to reach values of 12.63 hours.
Next, the scientists studied the mechanisms of ZnCDA accumulation in cancer tissues. Nanoparticles carrying CDA accumulated in a larger amount in the tumor compared to the control "pacifiers", while the accumulation rates in the liver and kidneys were similar. Scientists have suggested that STING activation leads to disruption of the vascular structure of the tumor, which facilitates the penetration of nanoparticles into tissues. Indeed, tissue staining showed a decrease in vascular density in the tumor by 46-57% in different lines. Scientists also found a sharp decrease in the number of endothelial cells.
Next, the scientists determined which cells are the target of ZnCDA. First of all, they checked whether interferon expression is necessary for therapeutic effect. Surprisingly, ZnCDA retains antitumor activity in mice with blocked interferon expression of the first type. At the same time, the blockade of interferon gamma led to a loss of ZnCDA activity. Further study of immune cells associated with interferon gamma showed that ZnCDA affects the activity of CD8+ T cells.
RNA sequencing of tumor-associated macrophages has demonstrated that ZnCDA therapy increases the expression of genes associated with activation of the immune response, as well as the expression of inflammatory cytokines. Signaling pathways of antigen presentation showed the greatest increase in activity in response to therapy. Thus, ZnCDA is able to provoke the development of an immune response even in "cold" tumors in which there is no natural course of inflammatory processes.
Finally, scientists have demonstrated the effectiveness of ZnCDA in mouse models of "cold" tumors that are not treated using classical methods of immune and radiotherapy. ZnCDA has shown efficacy in mouse models of pancreatic cancer and glioma.
The authors believe that ZnCDA has a high therapeutic potential, including in the treatment of complex diseases.
Article by Yang et al. Zinc cyclic di-AMP nanoparticles target and suppress tumours via endothelial STING activation and tumour-associated macrophage reinvigoration is published in the journal Nature Nanotechnology.
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