In his research program at Scripps Research, Paulson has studied the glycoproteins, proteins that are decorated with sugars for many years. Although these molecules have traditionally been difficult to understand, to limit their use in pharmaceutical applications, Paulson has experimented with new techniques to study and manipulate these molecules enigmatic.To extend the results, the scientists examined the activity of their compounds in blood samples from human patients with three types of B-cell lymphoma ? hairy cell leukemia, marginal zone lymphoma and chronic lymphocytic leukemia. Scientists have discovered that the compound also effectively destroy these and related B-cell patients.
?The advantage is that we already know a lot about how liposomes act in the body because they are approved drugs,? said Paulson. ?They have a circulatory half-life. They are formulated are not taken up by macrophages in the liver. So we just used the same formula, these ligands attached, and went directly into in vivo studies.?
Because of his previous research, Paulson knew that B cells have a receptor protein on their surface that have only recognized a few sugars found on glycoproteins. The team could create a viable therapeutic potential were those sugars to identify and target these cells?
In particular, the new study the team set out to attack B-cell lymphoma (including Hodgkin?s lymphoma and NHL), a type of cancer most commonly diagnosed in older people and those whose immune systems. Every year about 70,000 people are diagnosed with lymphoma in the United States alone, according to the American Cancer Society. While rituximab drug is often effective in treating the disease, 22,000 patients each year continue to die of malignant B cells
?[The method] worked immediately,? said Scripps Research Professor James Paulson, who led the research. ?We are very interested in advancing the technology to see if it would be applicable to the treatment of humans and investigate other applications for this type of targeting.?
The chemotherapy drug doxorubicin was chosen, which is used in the treatment of a wide range of cancers. First time in 1950, doxorubicin was isolated from bacteria found in soil samples taken from a 13th century castle in Italy. The team used a nanoparticle formulation of doxorubicin called Doxil, where the drug is encapsulated in liposomal nanoparticles, Paulson said that protects normal cells of the drug to reach cancer.
Normally Doxil is passively delivered to the tumor, leaving the tumor vasculature leaky, and the drug slowly leaks out to kill the tumor. But decorating the nanoparticles with the CD22 ligand, the team made up of nanoparticles in a sort of Trojan horse that is actively being targeted and taken from human B-cell lymphoma, the drug transport into the cell.
The research was funded by grants from the National Institute of Allergy and Infectious Diseases (NIAID) and National Institute of General Medical Sciences (NIGMS) National Institutes of Health (NIH).
Paulson and his colleagues decided to have groped a unique approach to the problem.
The first author of the article, ?In vivo targeting of B-cell lymphoma with glycan ligands to CD22,? Chen was Weihsu Scripps Research. In addition to Paulson, the authors were more Gladys Complete with Scripps Research, Darren Sigal, Alan Saven, Scripps Clinic and Medical Group, and Paul Crocker, University of Dundee (United Kingdom).
Scientists at The Scripps Research Institute have discovered a new way to target and destroy a tumor cell type. The results could lead to the development of new therapies to treat leukemia and related services.
In research, the team of their constituents in mice immunocompromised new compound that had been infected with B-cell lymphoma (Daudi Burkitt?s type). The team used two different formulations of the molecule, one decorated with two ligands per cent, the other with five percent. The mice received a single dose.
Encouraged by the results, the team is working to further improve the platform of drugs, looking for ways to increase the specificity of B cell targeting as well as exploring the use of technology with other chemotherapeutic agents.
The scientists then tried to see if they could detect residual cancer cells in the survivors, knowing that in a mouse that is paralyzed by the disease 95 percent of the cells in the bone marrow of cancer cells.
Scientists have combined two different types of molecules in one, with new and tried and true technology. Part of the therapeutic potential consisted of a specialized sugar (ligand) recognized by the B cell receptor, called CD22, expressed on the cell surface BE ?was attached to the surface of the other part of the therapeutic potential, a nanoparticle called ?liposomes?, loaded with a potent dose of a chemotherapy drug tried.
In the new research, Paulson and his colleagues have used some of the ideas from the laboratory of a problem with high medical importance ? a new way to target and destroy cancer cells.
The study, which appears in the June 10, 2010 edition of the journal Blood, demonstrated in animal models of the new technique was able to dramatically reduce B-cell lymphoma, a cancer of immune molecules called B lymphocytes
Normally, B cells provide an important immune function in blood to help the attack of infectious agents. But when B cells become cancerous, the problem is how to get them out from the crowd of other molecules in the body of the target for destruction, ideally without damaging the surrounding tissues.
?When we examined the bone marrow of those who had survived 100 days, we could not detect any [cancer cells],? said Paulson. ?Our detection limit is down by 0.3 percent. It ?was quite impressive.?
The results were remarkable. No mice in the control group lived at the end of the process to 100 days, but five of the eight mice receiving the high dose of the ligand compound survived.
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