Difference between revisions of "Team:Freiburg/Targeted Drug Delivery"

The scientific concept of specifically addressing diseases by drugs or agents directly targeting specific cells dates back to the 20th century. Paul Ehrlich (1854-1915), a German Nobel laureate, already dreamt of “magic bullets” which would only target harmful bacteria and disease-associated cells in the human body but would not harm the body itself ¹. After more than 100 years, the concept of targeted drug delivery isn’t merely a dream, it has become reality. Nowadays, clinically approved application of targeted drug therapy has become an integral part of cancer therapy. Targeted drug delivery relies on the release of therapeutic agents in a controlled manner to a certain site of the body, such as cancer cells. This can reduce systemic side effects due to lower overall concentration of the drugs in the whole body. Increasing the drug concentration only in the affected tissue, results in the improvement of the efficacy of the treatment². In contrast, drugs used in non-targeted cancer therapy are designed to kill all proliferating cells in an undiscriminating manner which means that healthy proliferating cells will be killed as well as. Thus, skin and intestinal epithelial cells will be destroyed during cancer therapy leading to side effects such as nephrotoxicity, hepatotoxicity, nausea, cardiotoxicity^3–5. Drug targeting requires the drug to fulfill certain criteria such as physicochemical stability in vivo, predictable concentration on the target site and specific binding to the target^6,7. Controlled drug delivery can increase patient compliance and the patients’ quality of life and survival outcome⁸. Until now, clinically approved agents used in targeted drug delivery are either humanized monoclonal antibodies also known as drug conjugated antibodies (ADCs) or small molecules, which activate immune cells to kill the targeted cells or activate apoptotic pathways through receptor binding^9–11. Humanized monoclonal antibodies target specific antigens found on cancer tissue and thus, deliver conjugated cytotoxic agents to cancer cells. However, ADCs and small molecules such as peptides are subjected to renal clearance and enzymatic degradation in the human body thus, hampering their efficacy and requiring continuous administration¹² To address those issues, some drugs must be conjugated to a vector or additional compounds in order to prevent degradation and to enhance solubility^13,14,15. Besides ADCs, nanoparticles represent a promising alternative approach eluding the short half-life of antibodies, providing the possibility of multifunctionality¹⁶. Nanoparticles include a wide spectrum of approaches and materials ranging from hydrogels¹⁷ to artificial liposomes¹⁸ to various polymers¹⁹ or even quantum dots²⁰. Although many new advances in this field are made considerable drawbacks still arise from expensive production, low-efficiency conjugation and high batch-to-batch variablitly²¹, resulting in only few approaches providing promising evidence in clinical applications²² Targeted drug delivery in therapy of cancer has advanced, however, to the best of our knowledge this treatment concept was not applied to other chronic diseases, such as ulcerative colitis, yet. Standard therapy for long-term, steroids-resistant or high grade ulcerative colitis consists of infliximab (Remicade®) which is a humanized monoclonal anti-TNF antibody. Once infliximab binds to TNF, it cannot bind to its receptor. Since this receptor is involved in activating immune cells, neutralizing TNF can reduced inflammatory reactions in the gut^23–25. However, infliximab inhibits TNF in the entire body, thus dampening immune reactions, causing serious infections²⁶, reactivating hepatitis B²⁷ and increasing the risk of lymphoma²⁸. Besides infliximab, azathioprine is an essential compound of long-term treatment in ulcerative colitis. ¹⁹ Azathioprine is given systemically and is converted in the liver to 6-mercaptopurine by glutathione S-transferase (GST) and then reaches all sites of the body through the blood stream. Thus, it is not a specific targeting drug. 6 mercaptopurine is the active compound that kills all proliferating cells, and thus dampens the immune system in the complete body causing the severe symptoms as mentioned before. Even worse, being a modifiying DNA agent it is regarded as a carcinogen. In the human digestive system, millions of bacteria and spores are inhabiting the colon. Those naturally occurring bacterial spores could be exploited as a potential targeting carrier to deliver the enzyme GST, which converts azathioprine to the active 6-mercaptopurine, locally only to the inflamed colon tissue and thus only dampening the immune system there. Bacillus subtilis is a non-pathogenic bacterium with probiotic features²⁹, which was approved by the Food and Drug Administration as GRAS organism – generally recognized as safe. Using this established probiotic as a carrier, makes it unlikely that the carrier causes side effects, such as inflammation. The potential use of targeted drug delivery in other medical fields than cancer therapy is promising. A method to deliver drugs in other chronic diseases has yet to be developed.