NEW YORK (Reuters Health) - A polymer of beta-amino esters used to deliver diphtheria toxin DNA to localized tumors suppresses tumor growth, according to a paper in the Proceedings of the National Academy of Sciences for November 9th.
Poly(beta-amino esters) are highly effective as gene delivery agents in vitro and are biodegradable, reports the research team, led by Dr. Daniel G. Anderson at the Massachusetts Institute of Technology in Cambridge, Massachusetts.
Their goal was to use a nonviral vector for tumor delivery of the A chain of diphtheria toxin DNA (DT-A), a potent inhibitor of protein synthesis that causes cell death, in a mouse xenograft model of prostate cancer. To that end, they screened a library of > 500 poly(beta-amino esters) and selected C32 as the one that transfected prostate cells with the highest efficiency while displaying no associated cytotoxicity.
They compared the ability of tumor growth inhibition by C32, a “state-of-the-art commercially available transfection polymer” jetPEI (polyethyleneimine), each bonded to DT-A, and naked DNA. When injected into tumors grown subcutaneously in mice and followed for 48 hour, the average transfection mediated by C32 was four times greater than that mediated by jetPEI and 26 times higher than naked DNA alone.
They injected C32, with 50 micrograms of DT-A DNA per injection and a 30:1 polymer/DNA ratio, or C32 bonded to control DNA every other day for a total of six injections into 15 tumors each. On average, tumor growth was suppressed twofold by C32/DT-A compared with C32 bonded to control DNA (p < 0.0001). Six of the tumors regressed in size, while three failed to grow.
In contrast, when they injected the DNA vectors intramuscularly into healthy muscle, naked DNA led to the highest levels of gene expression, followed by jetPEI. Transfection in healthy muscle was rarely observed with C32. Furthermore, jetPEI IM injection, but not naked DNA or C32, induced local toxicity.
“Because C32 transfects tumors locally at high levels, transfects healthy muscle poorly, and displays no toxicity, it may provide a vehicle for the local treatment of cancer,” the authors suggest. They surmise that C32-delivered DT-A would be associated with fewer toxic side effects and less damage to normal healthy surrounding tissues than currently available therapies.
The results are so promising that his team is in the process of setting up a phase I trial of this new technology, Dr. Anderson told Reuters Health.
In addition, “we’re in the process of creating a next generation of polymers, where for example we’ll add antibody fragments or ligands that we know are specific to certain tumors,” thus improving the vectors’ specificity.
Then ultimately, the researchers hope to generate an “ideal system where we can inject a polymer intravenously and it will go throughout the entire body, finding little pockets of tumors that have metastasized and transfect those specifically,” Dr. Anderson added.
Source: Proc Natl Acad Sci USA 2004;101:16028-16033. [ Google search on this article ]
MeSH Headings:Biological Therapy: DNA, Recombinant: Genetic Engineering: Genetic Techniques: Genetic Vectors: Investigative Techniques: Therapeutics: Gene Therapy: Analytical, Diagnostic and Therapeutic Techniques and EquipmentCopyright © 2002 Reuters Limited. All rights reserved. Republication or redistribution of Reuters content, including by framing or similar means, is expressly prohibited without the prior written consent of Reuters. Reuters shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. Reuters and the Reuters sphere logo are registered trademarks and trademarks of the Reuters group of companies around the world.
