Researchers at Ludwig-Maximilians University in Munich, with colleagues from Munich Technical University and Helmholtz Center Munich, engineered a gene that can generate anti-cancer agents deep inside solid cancerous tumors. The team led by Ludwig-Maximilians pharmacologist Manfred Ogris reported its findings online yesterday in the journal Molecular Therapy (paid subscription required).
Ogris (pictured right) and colleagues developed a method for delivering tumor necrosis factor alpha or TNF-alpha, a cell-signaling protein with the ability to kill cancer cells directly. To deliver TNF-alpha to the tumors, the researchers needed to find a way through the dense mass of blood vessels developed by tumors, but protected by a lymphatic system that diffuses anti-cancer agents.
In addition, TNF-alpha must be delivered directly to the tumors, and nowhere else. “Unfortunately, therapeutically effective amounts of TNF-alpha cannot be administered systemically, because this would lead to activation of, and damage to, all the vessels in the organism,” says Ogris. “For this reason, it is not possible to use this approach on tumors in internal organs or against dispersed metastases.”
The researchers decided to engineer a gene resembling TNF-alpha, but one that could produce larger amounts of the cancer-killing proteins. Once in the tumor, the gene would produce produce and secrete the agents in concentrations high enough to permeate the tumor’s mass of blood vessels, but remain localized to the tumor.
The team devised a plasmid — a form of DNA molecule that can replicate DNA in cells — that they added to nanoparticles. Lab tests with these nanoparticles show their DNA remained active and they could synthesize large amounts of TNF-alpha. However, the DNA nanoparticles had limited effects on tumor cells.
To enhance the DNA nanoparticles’ impact on tumor cells, Ogis and colleagues added the nanoparticles to the drug doxorubicin, which inhibits DNA replication and is used to treat ovarian cancer. The version of doxorubicin marketed under the brand name Doxil, made by Janssen Pharmaceuticals, is administered in tiny lipid bubbles about 100 nanometers in diameter (1 nanometer equals 1 billionth of a meter). By adding DNA nanoparticles to Doxil, the researchers found they could increase the impact of the DNA nanoparticles on tumor cells, but also increase their half-life as well as reduce side effects.
In tests on mice with neural (neuroblastoma) and liver tumors, Ogris’s team found the nanoparticles with the TNF-alpha gene concentrates in the tumor tissue, and in some cases stops tumor growth. They found this ability to inhibit tumor growth occurred even in mice already treated with three courses of Doxil, which suggests mice did not develop a resistance to this treatment.
In addition, the researchers found this strategy reduced the growth of metastasized cancers in mice, where cancer developed in the liver after initial tumors from neuroblastoma or colon cancer. “We now plan to optimize our gene delivery system,” says Ogris, “and hope that we can soon begin to plan preclinical tests of the new approach.”
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