Difference between revisions of "Team:Freiburg/Goals Approach"
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It is our goal to develop a new system of targeted drug delivery, where the drug only acts on the affected tissue and is not getting dispersed in the whole body. This approach will not harm the human body and has no negative side effects on it.<br> | It is our goal to develop a new system of targeted drug delivery, where the drug only acts on the affected tissue and is not getting dispersed in the whole body. This approach will not harm the human body and has no negative side effects on it.<br> | ||
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First, it is important to differ the terms prodrug and active drug in this system. A prodrug, precursor of a drug, must undergo chemical conversion by metabolic processes before becoming an active pharmacological agent, the active drug.<br><br> | First, it is important to differ the terms prodrug and active drug in this system. A prodrug, precursor of a drug, must undergo chemical conversion by metabolic processes before becoming an active pharmacological agent, the active drug.<br><br> | ||
Standard drug delivery systems are mostly oral. Patients take the pills and most of the prodrug will be activated by enzymes in the liver and distributed throughout the entire body. Thus, the activated drug will interact with healthy tissues and organs. With the standard approach, vulnerable organs like bone marrow or brain will show symptoms like lower production of blood cells or nausea, headache etc.<br> | Standard drug delivery systems are mostly oral. Patients take the pills and most of the prodrug will be activated by enzymes in the liver and distributed throughout the entire body. Thus, the activated drug will interact with healthy tissues and organs. With the standard approach, vulnerable organs like bone marrow or brain will show symptoms like lower production of blood cells or nausea, headache etc.<br> | ||
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The GST on the spore surface converts azathioprine in to 6-mercaptopurine. This has a toxic effect on cells in state of mitosis, because it replaces adenine and guanine in the DNA. This leads to a loss of function and therefore apoptosis of the diseased cell and the colon is able to regenerate. <br> | The GST on the spore surface converts azathioprine in to 6-mercaptopurine. This has a toxic effect on cells in state of mitosis, because it replaces adenine and guanine in the DNA. This leads to a loss of function and therefore apoptosis of the diseased cell and the colon is able to regenerate. <br> | ||
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Revision as of 04:10, 18 October 2016
Goals/Approach
“All Disease Begins in the Gut!” - Hippocrates
Some people are tough. And then there are some people, who have to fight against their own immune system- how tough is that?
In the case of ulcerative colitis patients, the mistakes made by the body’s immune system lead to cyclic inflammations and ulcers in rectum and colon. To treat this overreacted immune response, they rely on therapeutic options, which are distributed systemically. Furthermore they lead to horrible side effects, such as anemia, hysterical depression[1] and sadly, the risk for colon cancer increases enormously.
It is our goal to develop a new system of targeted drug delivery, where the drug only acts on the affected tissue and is not getting dispersed in the whole body. This approach will not harm the human body and has no negative side effects on it.
First, it is important to differ the terms prodrug and active drug in this system. A prodrug, precursor of a drug, must undergo chemical conversion by metabolic processes before becoming an active pharmacological agent, the active drug.
Standard drug delivery systems are mostly oral. Patients take the pills and most of the prodrug will be activated by enzymes in the liver and distributed throughout the entire body. Thus, the activated drug will interact with healthy tissues and organs. With the standard approach, vulnerable organs like bone marrow or brain will show symptoms like lower production of blood cells or nausea, headache etc.
The attempt to bypass the liver to avoid the systemic side effects, can be achieved by a specific activation of drugs at a specific area, i.e. the inflamed cells in the colon. We achieved this by using nanobodies, GST and the endospores of the bacterium Bacillus subtilis.
Through cloning and transformation of the Bacillus subtilis, we were able to customize the spores to our approach. We designed fusion proteins of the outer spore coat proteins dCotZ, dCotB, dCotG and dCgeA, containing a linker peptide with HA-Tag and a nanobody, which is able to bind to a specific marker. To enable the conversion of the prodrug to its active form, we also fused proteins with GST (glutathione S-transferase). Our end product is a spore combining these two functions, which is able to function as a complete new designed targeted drug delivery system, causing no negative side effects in the human body.
Our project's main target is the disease ulcerative colitis, an inflammatory bowel disease characterized by an enhanced expression of CEA (carcinoembryonic antigen) on affected tissue. Therefore, we considered it as the perfect marker. An engineered spore presents the nanobody against CEA, for the targeting of inflamed intestinal cells and the GST to locally activate the prodrug azathioprine.
The GST on the spore surface converts azathioprine in to 6-mercaptopurine. This has a toxic effect on cells in state of mitosis, because it replaces adenine and guanine in the DNA. This leads to a loss of function and therefore apoptosis of the diseased cell and the colon is able to regenerate.
Standard drug delivery systems are mostly oral. Patients take the pills and most of the prodrug will be activated by enzymes in the liver and distributed throughout the entire body. Thus, the activated drug will interact with healthy tissues and organs. With the standard approach, vulnerable organs like bone marrow or brain will show symptoms like lower production of blood cells or nausea, headache etc.
The attempt to bypass the liver to avoid the systemic side effects, can be achieved by a specific activation of drugs at a specific area, i.e. the inflamed cells in the colon. We achieved this by using nanobodies, GST and the endospores of the bacterium Bacillus subtilis.
Through cloning and transformation of the Bacillus subtilis, we were able to customize the spores to our approach. We designed fusion proteins of the outer spore coat proteins dCotZ, dCotB, dCotG and dCgeA, containing a linker peptide with HA-Tag and a nanobody, which is able to bind to a specific marker. To enable the conversion of the prodrug to its active form, we also fused proteins with GST (glutathione S-transferase). Our end product is a spore combining these two functions, which is able to function as a complete new designed targeted drug delivery system, causing no negative side effects in the human body.
Our project's main target is the disease ulcerative colitis, an inflammatory bowel disease characterized by an enhanced expression of CEA (carcinoembryonic antigen) on affected tissue. Therefore, we considered it as the perfect marker. An engineered spore presents the nanobody against CEA, for the targeting of inflamed intestinal cells and the GST to locally activate the prodrug azathioprine.
The GST on the spore surface converts azathioprine in to 6-mercaptopurine. This has a toxic effect on cells in state of mitosis, because it replaces adenine and guanine in the DNA. This leads to a loss of function and therefore apoptosis of the diseased cell and the colon is able to regenerate.
