The future of anti-cancer drugs may one day work like a laser-guided missile that hones in on its target. But if the missile misses, instead of harming good organs and tissues, the drug will simply break apart and be safely excreted from the body.
This “Magic Bullet” approach is the hope of researcher Dr. Clyde Ofner III from the department of Pharmaceutical Sciences and Director of the Graduate Program in Pharmaceutics who is one of the early researchers in an emerging field of antineoplastic agents.
(Left: Dr. Clyde Ofner III; Diagram: A "Magic Bullet" will exploit the advantage of poor cellular junctions in tumors to build up in a passive accumulation but avoid healthy tissues.)
Dr. Ofner recently returned from Nuremberg, Germany, where he was invited to share his research on gelatin-methotrexate conjugates with the international scientific community at the EHRLICH II -- 2nd World Conference on Magic Bullets that took place from October 3-5. The conference is named after Paul Ehrlich, who is recognized for coining the term "Magic Bullets" and presented his ideas about chemotherapy at his Nobel talk 100 years ago. The first conference was held in 2004.
“The reason we say ‘magic’ is because medicine doesn’t work that way,” said Dr. Ofner. “All medicines have side effects, especially cancer drugs. Some people die from the drug before the drug can kill off the cancer. In fact, most anti-cancer drugs are poisons.”
Through macro molecular conjugate drug delivery, Dr. Ofner is researching whether drugs can be safely targeted at tumors in a passive manner that uses the body’s processes. This is different from a more common approach that uses molecules attached to the drugs to bind and, therefore, target structures found on cancer cells.
“The idea with macro molecular conjugate drug delivery is not only to tinker with the cancer cells, but to also influence the body,” Dr. Ofner explained.
Dr. Ofner has three stages of drug design for these conjugates. He was assisted by three former graduate students Bill Bowman PhD’01, Chao-Shen Cheng PhD’05 and Karen Pica PhD’05, who did research in the first two stages, and with current graduate and undergraduate students, is now embarking on studies of the third.
In the first stage, the drug and its carrier are designed to circulate in the body for longer than normal times. By using a high molecular weight and longer circulation, the entire conjugate has an opportunity to zero in on solid tumors by taking advantage of poor cellular junctions in tumors to build up in a passive accumulation but avoid healthy tissues. The mechanism is based on what’s called the Enhanced Permeability and Retention (EPR) effect.
“There are two big potential pluses with being able to use a high molecular weight,” Dr. Ofner said. “We believe we will be able to target drug delivery and minimize side effects.”
The second stage is what makes Dr. Ofner’s research exciting--the potential for the antineoplastic agent to biodegrade if it does not find a tumor and avoid toxicities observed with other macro molecular carriers under investigation and avoid toxicities of the anti-cancer drug.
“We use a biodegradable carrier. Most researchers have taken the approach of using synthetic polymers, but they don’t get broken down by the body,” Ofner said. “Those models also have to keep a lower size to be filtered out through the kidneys. We are using a much higher molecular weight and the higher the size you use, the more we anticipate will build up in the tumor.”
The final stage of design will explore the bond between the drug and the carrier. His recent research has shown that a new bond is needed because the link was too strong and did not effectively release the drug. In the last year or two, Dr. Ofner and graduate students Brian Rhodes and Darren Wu are now exploring the use of an acid cleavable conjugate bond.
“We always had the first two parts,” he said. “We are now moving on with selective pH release. The drug is not expected to release in the blood stream because it has neutral pH. Instead, when it gets into the tumor there is a slightly acidic pH that will cause the drug to be released.”
So far, his work has been in vitro using controlled pH and enzymes as well as cell cultures but plans are underway for animal studies.
Dr. Ofner works collaboratively on campus with Dr. Ruy Tchau and Dr. Bin Chen to utilize their pharmacology and toxicology backgrounds but who are also in the Department of Pharmaceutical Sciences. Despite being slated to speak and moderate a session at EHRLICH II in New/Known Targets and Mechanisms, Dr. Ofner says his work has been classified as drug delivery, experimental therapeutics, and even translational research. In any classification, it falls out of mainstream medical research.
“In general, there are a few labs doing research in macro molecular conjugate drug delivery. It started about 20 years ago and only three have been approved for market. A few others are in phase one, two, or three clinical trials. All but one are using synthetic polymers,” Dr. Ofner said. “We are one of only a couple labs that are conducting research on biodegradable anti-cancer drugs.”