Team:Freiburg/Targeted Drug Delivery
Targeted Drug Delivery - Current State
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.
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, cardiotoxicity3–5.
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 target6,7. 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 binding9–11. 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 solubility13,14,15.
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 target6,7. 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 binding9–11. 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 solubility13,14,15.
Figure 1. Antibody drug conjugates.
An antibody facilitates the targeting of disease-associated antigens. When linked to a cytotoxic agent antibody drug conjugates enable to specifically target affected cell.
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
Figure 2. Nanoparticles in targeted drug delivery.
Polymer-based nanoparticles offer the advantage of carrying multiple functionalities increasing their flexibility for various applications.
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-TNFα antibody. Once infliximab binds to TNFα, it cannot bind to its receptor. Since this receptor is involved in activating immune cells, neutralizing TNFα can reduce inflammatory reactions in the gut23–25. However, infliximab inhibits TNFα 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. 24 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.
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.
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.
References
1. Bae, Y. H. & Park, K. Targeted drug delivery to tumors: Myths, reality and possibility. J. Control. Release 153, 198–205 (2011).
2. Vasir, J. K. & Labhasetwar, V. Targeted drug delivery in cancer therapy. Technol. Cancer Res. Treat. 4, 363–374 (2005).
3. Florea, A.-M. & Büsselberg, D. Cisplatin as an anti-tumor drug: cellular mechanisms of activity, drug resistance and induced side effects. Cancers (Basel). 3, 1351–71 (2011).
4. Schimmel, K. J. M., Richel, D. J., van den Brink, R. B. A. & Guchelaar, H. J. Cardiotoxicity of cytotoxic drugs. Cancer Treatment Reviews 30, 181–191 (2004).
5. Zorzi, D. et al. Chemotherapy-associated hepatotoxicity and surgery for colorectal liver metastases. Br. J. Surg. 94, 274–86 (2007).
6. Chourasia, M. K. & Jain, S. K. Pharmaceutical approaches to colon targeted drug delivery systems. Journal of Pharmacy and Pharmaceutical Sciences 6, 33–66 (2003).
7. Hunt, C. A., MacGregor, R. D. & Siegel, A. R. Drug Delivery engineering targeted in vivo drug delivery. I. The Physiological and physiocemical principles governing opportunities and limitations. 333–344 (1986).
8. Coombes, R. et al. Survival and safety of exemestane versus tamoxifen after 2-3 years’ tamoxifen treatment (Intergroup Exemestane Study): a randomised controlled trial. Lancet 369, 559–570 (2007).
9. Adams, G. P. & Weiner, L. M. Monoclonal antibody therapy of cancer. Nat. Biotechnol. 23, 1147–57 (2005).
10. Gutheil, J. C. et al. Targeted antiangiogenic therapy for cancer using Vitaxin: a humanized monoclonal antibody to the integrin alphavbeta3. Clin. Cancer Res. 6, 3056–3061 (2000).
11. Nahta, R., Hung, M. C. & Esteva, F. J. The HER-2-Targeting Antibodies Trastuzumab and Pertuzumab Synergistically Inhibit the Survival of Breast Cancer Cells. Cancer Res. 64, 2343–2346 (2004).
12. Firer M.A., G. G. Targeted drug delivery for cancer therapy: The other side of antibodies. J. Hematol. Oncol. 5, no pagination (2012).
13. Allen, T. M. Long-circulating (sterically stabilized) liposomes for targeted drug delivery. Trends in Pharmacological Sciences 15, 215–220 (1994).
14. Malam, Y., Loizidou, M. & Seifalian, A. M. Liposomes and nanoparticles: nanosized vehicles for drug delivery in cancer. Trends in Pharmacological Sciences 30, 592–599 (2009).
15. Perez, H. L. et al. Antibody-drug conjugates: Current status and future directions. Drug Discov. Today 19, 869–881 (2014).
16. Singh, R. & Lillard, J. W. Nanoparticle-based targeted drug delivery. Exp. Mol. Pathol. 86, 215–223 (2009).
17. Hoare, T. R. & Kohane, D. S. Hydrogels in drug delivery: Progress and challenges. Polymer (Guildf). 49, 1993–2007 (2008).
18. Sercombe, L. et al. Advances and challenges of liposome assisted drug delivery. Front. Pharmacol. 6, 1–13 (2015).
19. Liechty, W. B., Kryscio, D.R., Slaughter, B. V. and Peppas, N. A. Polymers for drug delivery systems. Annu. Rev. Chem. Biomol. Eng. 1, 149–173 (2010).
20. Misra, R. D. K. Quantum dots for tumor-targeted drug delivery and cell imaging. Nanomedicine 3, 271–274 (2008).
21. Kamaly, N., Xiao, Z., Valencia, P. M., Radovic-Moreno, A. F. & Farokhzad, O. C. Targeted polymeric therapeutic nanoparticles: design, development and clinical translation. Chem. Soc. Rev. 41, 2971 (2012).
22. Desai, N. Challenges in development of nanoparticle-based therapeutics. AAPS J. 14, 282–95 (2012).
23. Kirman, I., Whelan, R. L. & Nielsen, O. H. Infliximab: mechanism of action beyond TNF-alpha neutralization in inflammatory bowel disease. Eur. J. Gastroenterol. Hepatol. 16, 639–641 (2004).
24. Luan, Z. J. et al. Treatment efficacy and safety of low-dose azathioprine in chronic active ulcerative colitis patients: A meta-analysis and systemic review. J. Dig. Dis. (2016). doi:10.1111/1751-2980.12386
25. Reinisch, W. et al. Long-term infliximab maintenance therapy for ulcerative colitis: The ACT-1 and -2 extension studies. Inflamm. Bowel Dis. 18, 201–211 (2012).
26. Hirsch, J. et al. Case Report Q Fever Risk in Patients Treated with Chronic Antitumor Necrosis Factor-Alpha Therapy. Case Rep. 2016, (2016).
27. Pérez-Alvarez, R. et al. Hepatitis B virus (HBV) reactivation in patients receiving tumor necrosis factor (TNF)-targeted therapy: analysis of 257 cases. Medicine (Baltimore). 90, 359–71 (2011).
28. Mackey, A. C., Green, L., Liang, L. C., Dinndorf, P. & Avigan, M. Hepatosplenic T cell lymphoma associated with infliximab use in young patients treated for inflammatory bowel disease. J Pediatr Gastroenterol Nutr 44, 265–267 (2007).
29. Horosheva, T. V., Vodyanoy, V. & Sorokulova, I. Efficacy of Bacillus probiotics in prevention of antibiotic-associated diarrhoea: a randomized, double-blind, placebo-controlled clinical trial. JMM Case Reports 1, e004036–e004036 (2014).
1. Bae, Y. H. & Park, K. Targeted drug delivery to tumors: Myths, reality and possibility. J. Control. Release 153, 198–205 (2011).
2. Vasir, J. K. & Labhasetwar, V. Targeted drug delivery in cancer therapy. Technol. Cancer Res. Treat. 4, 363–374 (2005).
3. Florea, A.-M. & Büsselberg, D. Cisplatin as an anti-tumor drug: cellular mechanisms of activity, drug resistance and induced side effects. Cancers (Basel). 3, 1351–71 (2011).
4. Schimmel, K. J. M., Richel, D. J., van den Brink, R. B. A. & Guchelaar, H. J. Cardiotoxicity of cytotoxic drugs. Cancer Treatment Reviews 30, 181–191 (2004).
5. Zorzi, D. et al. Chemotherapy-associated hepatotoxicity and surgery for colorectal liver metastases. Br. J. Surg. 94, 274–86 (2007).
6. Chourasia, M. K. & Jain, S. K. Pharmaceutical approaches to colon targeted drug delivery systems. Journal of Pharmacy and Pharmaceutical Sciences 6, 33–66 (2003).
7. Hunt, C. A., MacGregor, R. D. & Siegel, A. R. Drug Delivery engineering targeted in vivo drug delivery. I. The Physiological and physiocemical principles governing opportunities and limitations. 333–344 (1986).
8. Coombes, R. et al. Survival and safety of exemestane versus tamoxifen after 2-3 years’ tamoxifen treatment (Intergroup Exemestane Study): a randomised controlled trial. Lancet 369, 559–570 (2007).
9. Adams, G. P. & Weiner, L. M. Monoclonal antibody therapy of cancer. Nat. Biotechnol. 23, 1147–57 (2005).
10. Gutheil, J. C. et al. Targeted antiangiogenic therapy for cancer using Vitaxin: a humanized monoclonal antibody to the integrin alphavbeta3. Clin. Cancer Res. 6, 3056–3061 (2000).
11. Nahta, R., Hung, M. C. & Esteva, F. J. The HER-2-Targeting Antibodies Trastuzumab and Pertuzumab Synergistically Inhibit the Survival of Breast Cancer Cells. Cancer Res. 64, 2343–2346 (2004).
12. Firer M.A., G. G. Targeted drug delivery for cancer therapy: The other side of antibodies. J. Hematol. Oncol. 5, no pagination (2012).
13. Allen, T. M. Long-circulating (sterically stabilized) liposomes for targeted drug delivery. Trends in Pharmacological Sciences 15, 215–220 (1994).
14. Malam, Y., Loizidou, M. & Seifalian, A. M. Liposomes and nanoparticles: nanosized vehicles for drug delivery in cancer. Trends in Pharmacological Sciences 30, 592–599 (2009).
15. Perez, H. L. et al. Antibody-drug conjugates: Current status and future directions. Drug Discov. Today 19, 869–881 (2014).
16. Singh, R. & Lillard, J. W. Nanoparticle-based targeted drug delivery. Exp. Mol. Pathol. 86, 215–223 (2009).
17. Hoare, T. R. & Kohane, D. S. Hydrogels in drug delivery: Progress and challenges. Polymer (Guildf). 49, 1993–2007 (2008).
18. Sercombe, L. et al. Advances and challenges of liposome assisted drug delivery. Front. Pharmacol. 6, 1–13 (2015).
19. Liechty, W. B., Kryscio, D.R., Slaughter, B. V. and Peppas, N. A. Polymers for drug delivery systems. Annu. Rev. Chem. Biomol. Eng. 1, 149–173 (2010).
20. Misra, R. D. K. Quantum dots for tumor-targeted drug delivery and cell imaging. Nanomedicine 3, 271–274 (2008).
21. Kamaly, N., Xiao, Z., Valencia, P. M., Radovic-Moreno, A. F. & Farokhzad, O. C. Targeted polymeric therapeutic nanoparticles: design, development and clinical translation. Chem. Soc. Rev. 41, 2971 (2012).
22. Desai, N. Challenges in development of nanoparticle-based therapeutics. AAPS J. 14, 282–95 (2012).
23. Kirman, I., Whelan, R. L. & Nielsen, O. H. Infliximab: mechanism of action beyond TNF-alpha neutralization in inflammatory bowel disease. Eur. J. Gastroenterol. Hepatol. 16, 639–641 (2004).
24. Luan, Z. J. et al. Treatment efficacy and safety of low-dose azathioprine in chronic active ulcerative colitis patients: A meta-analysis and systemic review. J. Dig. Dis. (2016). doi:10.1111/1751-2980.12386
25. Reinisch, W. et al. Long-term infliximab maintenance therapy for ulcerative colitis: The ACT-1 and -2 extension studies. Inflamm. Bowel Dis. 18, 201–211 (2012).
26. Hirsch, J. et al. Case Report Q Fever Risk in Patients Treated with Chronic Antitumor Necrosis Factor-Alpha Therapy. Case Rep. 2016, (2016).
27. Pérez-Alvarez, R. et al. Hepatitis B virus (HBV) reactivation in patients receiving tumor necrosis factor (TNF)-targeted therapy: analysis of 257 cases. Medicine (Baltimore). 90, 359–71 (2011).
28. Mackey, A. C., Green, L., Liang, L. C., Dinndorf, P. & Avigan, M. Hepatosplenic T cell lymphoma associated with infliximab use in young patients treated for inflammatory bowel disease. J Pediatr Gastroenterol Nutr 44, 265–267 (2007).
29. Horosheva, T. V., Vodyanoy, V. & Sorokulova, I. Efficacy of Bacillus probiotics in prevention of antibiotic-associated diarrhoea: a randomized, double-blind, placebo-controlled clinical trial. JMM Case Reports 1, e004036–e004036 (2014).
