"As a general strategy, the indiscriminate delivery of drugs into every cell of the body for the treatment of a few specific pathologic cells, such as cancer cells, is a thing of the past," said Philip Low, the Ralph C. Corley Distinguished Professor of Chemistry. "Most new drugs under development will be targeted directly to the pathologic, disease-causing cells, and we have shed light on the details of one mechanism by which this is achieved."
An understanding of the cellular process that leads to the release of targeted drugs is a major advancement for the field, he said.
"This will help others interested in targeted drug therapy," said Low, who also is founder and chief science officer of Endocyte Inc., a Purdue Research Park-based company. "The knowledge applies not only to the treatment of cancer. The understanding of how to deliver and unload a cancer drug can be extrapolated to all sorts of other diseased cells. The uptake pathways are similar in cells involved in arthritis, multiple sclerosis, psoriasis and Crohn's disease."
Interest in how drugs are released after they enter their targeted cell led Low and his team to develop a color-coded method to visualize the cellular mechanisms. Jun Yang, a postdoctoral research associate in Low's research group, together with Ji-Xin Cheng, an assistant professor in the Department of Biomedical Engineering, and his graduate student Hongtao Cheng, developed this method using a technique called fluorescence resonance energy transfer imaging.
"The drug turns from red to green when it is released inside the cell, clearly illuminating the process," Yang said. "This is the first optical method to be developed to monitor this release. The main promise of this method is that it does not damage the cells being studied. Therefore, we are able to observe the process under true physiological conditions and watch it right as it is happening."
This research, funded by Endocyte, will be detailed in a paper in Tuesday's (Sept. 12) issue of the Proceedings of the National Academy of Sciences and is currently available online.
In targeted drug therapy, drugs are linked to molecules that are used in excess by pathologic cells, for example a required nutrient, in order to transport drugs directly to the targeted cells while avoiding significant delivery of the toxic drug to normal cells. A commonly used agent, referred to as a ligand, is the vitamin folic acid. Cancer cells need folic acid to grow and divide and, therefore, have developed abundant receptors to capture it. These receptors are largely absent in normal cells. This means folic acid, and the drug linked to it, are attracted to the pathologic cells and are harmless to healthy cells, Low said.
Low led the team that discovered this folate-targeted treatment method in 1991 and the receptor-targeted technology is proprietary to Endocyte.
"It is desirable to have the drug released from the ligand, folic acid, once the folate-linked complex enters the cell," Yang said. "This 'conditional drug release' is usually realized by attaching folate to the drug through a linker that falls apart inside the cell. There were several linkers in common use, but with mixed efficiency. In this study we undertook to interrogate the full details of this breakdown process."
Yang examined receptor endocytosis, the process by which cells absorb materials — such as a drug attached to folic acid — that have been captured at special sites, called receptors, on the cell surface. The compound is then broken down and processed, releasing the drug.
One of the key mechanisms of this breakdown is disulfide reduction, which involves the breaking of chemical bonds. It was thought that disulfide reduction relied on the movement of the material along microtubules, hollow tubelike structures, and fusion with special digestive-enzyme containing compartments within the cell called lysosomes. However, the research showed that disulfide reduction occurred even when such components were removed from the process.
By inactivating different cellular components, Yang discovered which components are essential to the disulfide reduction process.
"It was surprising to learn that many other components of the cell, aside from those previously assumed to be responsible, were capable of releasing the drug from folic acid," Yang said. "This significantly increases the opportunity for the drug to be released. For instance, we used to believe it had to get to a specific location to be released, and now we know it can happen almost anywhere during endocytosis."
The mechanisms, locations and cellular components involved in the release of drugs within a cell had been under debate for several years, Low said.
"This is the definitive statement on how drugs are released within a cell," he said. "We will use this knowledge to develop better receptor-targeted drug therapies to treat cancer and other diseases."
Low and Yang worked with scientists from the Department of Chemistry, Weldon School of Biomedical Engineering and Endocyte, and used facilities at the Oncological Sciences Center, part of the Purdue Cancer Center, and Bindley Bioscience Center at Purdue's Discovery Park.
Endocyte Inc. develops receptor-targeted therapeutics for the treatment of cancer and autoimmune diseases. Endocyte has three compounds in Food and Drug Administration-regulated clinical trials: EC20, a targeted diagnostic agent that is in Phase II studies; EC17, a targeted-hapten therapy that is in Phase I studies; and EC145, a targeted cytotoxic agent that is in phase I studies. Endocyte has licensed its vitamin-targeting technology to Bristol-Myers Squibb to target Bristol-Myers Squibb's proprietary epothilone cancer chemotherapeutic agents.Writer: Elizabeth K. Gardner, (765) 494-2081, email@example.com
Elizabeth K. Gardner | EurekAlert!
Link Discovered between Immune System, Brain Structure and Memory
26.04.2017 | Universität Basel
Researchers develop eco-friendly, 4-in-1 catalyst
25.04.2017 | Brown University
More and more automobile companies are focusing on body parts made of carbon fiber reinforced plastics (CFRP). However, manufacturing and repair costs must be further reduced in order to make CFRP more economical in use. Together with the Volkswagen AG and five other partners in the project HolQueSt 3D, the Laser Zentrum Hannover e.V. (LZH) has developed laser processes for the automatic trimming, drilling and repair of three-dimensional components.
Automated manufacturing processes are the basis for ultimately establishing the series production of CFRP components. In the project HolQueSt 3D, the LZH has...
Reflecting the structure of composites found in nature and the ancient world, researchers at the University of Illinois at Urbana-Champaign have synthesized thin carbon nanotube (CNT) textiles that exhibit both high electrical conductivity and a level of toughness that is about fifty times higher than copper films, currently used in electronics.
"The structural robustness of thin metal films has significant importance for the reliable operation of smart skin and flexible electronics including...
The nearby, giant radio galaxy M87 hosts a supermassive black hole (BH) and is well-known for its bright jet dominating the spectrum over ten orders of magnitude in frequency. Due to its proximity, jet prominence, and the large black hole mass, M87 is the best laboratory for investigating the formation, acceleration, and collimation of relativistic jets. A research team led by Silke Britzen from the Max Planck Institute for Radio Astronomy in Bonn, Germany, has found strong indication for turbulent processes connecting the accretion disk and the jet of that galaxy providing insights into the longstanding problem of the origin of astrophysical jets.
Supermassive black holes form some of the most enigmatic phenomena in astrophysics. Their enormous energy output is supposed to be generated by the...
The probability to find a certain number of photons inside a laser pulse usually corresponds to a classical distribution of independent events, the so-called...
Microprocessors based on atomically thin materials hold the promise of the evolution of traditional processors as well as new applications in the field of flexible electronics. Now, a TU Wien research team led by Thomas Müller has made a breakthrough in this field as part of an ongoing research project.
Two-dimensional materials, or 2D materials for short, are extremely versatile, although – or often more precisely because – they are made up of just one or a...
20.04.2017 | Event News
18.04.2017 | Event News
03.04.2017 | Event News
26.04.2017 | Materials Sciences
26.04.2017 | Agricultural and Forestry Science
26.04.2017 | Physics and Astronomy