Special delivery for drugs

Prof. Yechezkel Barenholz co-developed the first Israeli cancer drug, and was honored recently with a 70th birthday conference.

By JUDY SIEGEL-ITZKOVICH
Yechezkel Berenholz (photo credit: Judy Siegel-Itzkovich)
Yechezkel Berenholz
(photo credit: Judy Siegel-Itzkovich)
For a man who never wanted to be a physician, Prof. Yechezkel Barenholz of Hebrew University-Hadassah Medical School – recently honored on his 70th birthday with a scientific meeting (“Liposome in Jerusalem 2011” conference) about his favorite field – has had a significant impact on an important and promising field in medical research and healthcare.
Carrying on the study of liposomes by the late British scientist Dr. Alec Bangham, Barenholz – one of Israeli’s leading biochemists – and his teams of developers went on to get nearly three dozen discoveries patented, hundreds of research articles published, and many more cited in the scientific literature.
Liposomes are tiny fat globules covered with one or more bilayered fat membranes, first photographed with a microscope in the middle of the 19th century. But was only in 1961 that Bangham, (who was later knighted by the queen) described what they do and characterized them.
With the word liposome derived from two Greek words, lipid (meaning fat) and soma (meaning body), these polymeric nanoparticles may not look like much, but they pack a punch.
Already in 1964, as a young Tel Aviv-born student needing to support himself, Barenholz took a lab job making enzyme substrates to study enzymes involved in lipid metabolism and lipid-related diseases. His love affair with the tiny spheres of fat – which would continue through his chronological-but-ignored retirement age – then began. Today, large numbers of women around the world who suffer from ovarian or breast cancer are treated with Doxil.
This liposome drug is based on a generic drug more effectively delivered to the tumor inside the fat globules, which Barenholz developed with Prof. Alberto Gabizon, formerly of the Hadassah University Medical Center and currently chief of oncology at Shaare Zedek Medical Center in Jerusalem. The lives of patients with these and other types of cancers and other diseases are extended and their quality much improved, thanks to the liposome form of the generic chemotherapy drug doxorubicin.
“I wanted to be a chemist, but my grades weren’t high enough,” says Barenholz – described by colleagues as both “brilliant and modest.” So for his earliest academic work, he studied biology, which today requires higher grades than chemistry. “I am not sorry, as I learned a lot of chemistry on my own that has helped in my career. I learned from life that there is no reason to look back and regret.”
He earned his bachelor’s (natural sciences, microbiology and biochemistry), master’s and doctoral degrees (biochemistry) from HU.
Pointing to a corner in the medical school’s biochemistry department, he says: “This is where I did the work for my doctorate.” He was a pioneer in the study of sphingolipids – a class of lipid compounds discovered in brain extracts 140 years ago that play important roles in signal transduction and cell recognition – and how they break down. Having started with liposomes as a model for cell membranes, by 1980, Barenholz went into liposomes’ applications.
He related at the liposome conference at Kibbutz Ma’aleh Hahamisha (attended by over 300 liposome specialists from the US to China to honor him, learn and lecture) how he got to know Bangham and get permission to study under him. In 1969, in the second year of his Ph.D.
studies, Barenholz asked his HU mentor, Prof. Shimon Gatt, to find him a place where he could study lipid biophysics. He suggested the Babraham Animal Research Institute near Cambridge, UK; one lab Barenholz applied to was run by Rex Dawson and the second by Bangham (who had been trained as a pathologist). Having quickly learned that working with Dawson would not give him enough experience in lipid biophysics, he yearned to join Bangham’s team. But it was no simple matter to win his favor.
The young Israeli came to England with his wife Hanna and their eldest daughter Chagit; three more would be born later. He heard that an established American scientist was also interested in doing work on liposomes with Bangham, who asked the man why he wanted to work with him. “Sure,” said Barenholz’s US competitor. “We’re both interested in liposomes,” to which Bangham replied: “Who said I am interested in liposomes? My main interest is in gardening.” The American was turned down.
Thinking quickly, when Bangham – who is considered the “father of liposomes” – tested Barenholz on the subject, he asked the Israeli the same question. Having worked in gardening for a while at Kibbutz Yotvata, the man from Hebrew University quickly said they had gardening in common. Barenholz was accepted – and became a close colleague and friend, and even hosted him in Israel 18 years ago when the Briton was 76. Barenholz, known to everyone as “Chezy,” fondly remembers his Cambridge mentor, who had been the British Army’s chief pathologist in Mandatory Palestine in early 1948 and died a year ago at the age of 93.
The Doxil liposomes were designed with a natural ability to target cancer. The endothelial wall of all healthy human blood vessels is made by endothelial cells bound together by tight junctions, preventing any large particle in the blood from leaking out. But tumor blood vessels don’t have the same sealing ability and are leaky. Liposomes of certain sizes can slowly leave these special blood vessels and permeate the tumor sites selectively from the blood. However, they are not kept in the bloodstream and do not leak out through the endothelial walls in healthy blood vessels.
These special nano liposomes are referred to as “stealth liposomes” due to the coating of polyethylene glycol that helps them avoid detection by the body’s immune system. Therefore, they can circulate in the blood for a long time, during which they can leak out to the tumor tissue. These passively targeted liposomes can zoom in and reach tumors and inflammation sites to deliver drugs, making naturally toxic chemotherapy drugs much less so by delivering them only to diseased tissue.
Given by infusion, Doxil works better than doxorubicin, and can extend life by 25 percent to 33% compared to the next-best treatment.
Patients also have a higher quality of life and survive longer, as it targets the cancer cells, says Barenholz. It isn’t a cure, but patients suffer from many fewer side effects: They don’t feel nauseous or vomit, and don’t lose their hair.
Doxil, which currently totals almost $600 million in annual sales around the world, will soon lose its patent protection. It has more recently been recognized by the authorities for the treatment of multiple myeloma, Kaposi’s syndrome (a tumor that may affect AIDS patients) and other cancers. Doxil is best given in tandem with other types of chemotherapy that function differently, he says in an interview with The Jerusalem Post after the conference.
He is also trying to integrate it with immunotherapy, which is the treatment of disease by inducing, enhancing or suppressing an immune response of antibodies in the body. But while rather promising, this technique is very difficult because the disease is usually diagnosed too late for the immune system to react. Personalized medicine, in which biomarkers are identified in patients according to sub-groups of cancer types is, however, the wave of the future, says Barenholz, who regards the injection of adult stem cells as another possible avenue.
“For many years, cancer was regarded as ‘cancer.’ Then it was characterized according to the organ or tissue that was affected. Today, it is done by substances in the blood and types of cells,” he explains.
“Subgrouping is beneficial because people whom a certain treatment will help will get a specific treatment instead of using it on everybody. This will bring down prices. Targeting a specific subgroup also raises success rates, helping get official approval for the drug, and reduces toxicity because the drugs are more suited to the patient treated,” says Barenholz, whose mother contracted uterine cancer in her 60s but lived into her 90s.
Barenholz and his teams, many of which work in startup companies around the country, have other liposome ideas up their sleeves. They have already tested in mice – which are the best animal model for tumors – a combination of two generic drugs called topotecan and vincristrin in a single liposome for more effective delivery. He shares a patent for the product, LipoViTo, with his student Danny Zucker. “It isn’t enough to show the US Food and Drug Administration that a drug candidate is merely less toxic and has fewer side effects than others; one has to show it works better.”
He is also working with New York University obstetrics anesthesiologist Dr. Gil Grant on developing local anesthesia for acute pain after surgery or from chest trauma and coughing as a result of pneumonia. Ordinary local anesthetics disappear rapidly. Morphine and other opiates could be used, but these work via the brain and thus affect mental functioning.
The two are using a hydrogel with liposomes to delivery anesthesia in the hope that the combination will safely minimize pain for longer periods.
Barenholz and colleagues are aiming to improve influenza vaccines, as conventional ones become less protective as the user gets older, or is younger but has a weak immune system, opening them up to serious and even fatal flu complications. The biggest challenge for vaccine companies is the development of improved flu vaccines, and increasing the number of people who develop an immune response to it. Other challenges include cutting the dosage of vaccine to extend the world’s supply and provide an alternative, needle-free and more “friendly” method of administration.
Thus a startup named NasVax, of which Barenholz is a cofounder, was established with two workers seven years ago under the “umbrella” of the Meytav Technological Incubator in Kiryat Shmona, and then moved to the Kiryat Weizmann Science Park in Nes Ziona.
Barenholz notes that there are often shortages of conventional flu vaccine, and many people avoid getting vaccinated because they are afraid of injections. NasVax is thus working on a nasal-spray vaccine and improved injectible vaccines that will offer more protection, especially for the elderly.
Barenholz also set up a company named LipoCure, developing liposomes to treat autoimmune rheumatoid arthritis, which produces widespread inflammation; the fat globules help lubricate the joints. He is also directing work on better drugs against multiple sclerosis, which despite the existing drugs – most of which are based on Israeli research – still has an estimated untouched world market of $5 billion and needs even better medications to minimize neurological attacks. Over all, he now heads a teams with a total of 25 people.
The conference participants, most of whom know each other because of the relatively few specialists in liposome research, reported on a wide variety of potential uses, including drugs for heart attack repair, blood triglyceride reduction, gene therapy and eye disease. It took a heavy, 242-page book of extracts to summarize them all.
Instead of keeping all his royalties for himself, Barenholz generously established a fund some years ago called the Barenholz Prizes that provides scholarships to young researchers. This year, two international prizes were given at the “Liposome in Jerusalem” conference. The winners were Dr. Roy Ziblat, currently of Harvard University’s Institute for Biologically Inspired Engineering, for his work (done in Israel) on cholesterol nucleation, and Dr. Tamar Harel- Adar of Ben-Gurion University of the Negev, for her work on “fooling the heart” into repairing itself using liposomal and lipid-based delivery systems. Two other prizes were given to Ph.D. students of the Hebrew University – one to Shaul Lapidot of the Faculty of Agriculture at the Hebrew University for developing a method of using paper mill waste to produce ecologically friendly, industrial foams as nano crystalline cellulose from renewable resources, and the other to Oded Yaakobi for his contributions to the field of high-power lasers and telecommunication.
The HU medical faculty biochemist naturally enjoys the royalties he earns from Doxil and other developments, but declares that there are things more important to him than money. “It takes a phenomenal amount of motivation to travel the uphill path that leads to something that works. I really enjoy helping people and creating something useful and effective.”