Positively charged lipid-based nanoparticles are known to trigger strong immune responses when injected into the body, which can be problematic when attempting to use this type of nanoparticle as a drug delivery vehicle. Now, researchers at Colorado State University, led by Steven Dow, Ph.D., D.V.M., have taken advantage of this effect to boost the activity of a DNA-based anticancer vaccine. This work appears in the journal Cancer Gene Therapy.
Cancer vaccines have the promise to harness the body’s immune system to kill cancer and to prevent tumors from metastasizing, but the results of human clinical trials for a variety of cancer vaccines have produced mixed results. And while DNA-based vaccines work well in animal models, they have done poorly in humans, particularly at preventing the spread of cancer to the lungs. Some studies suggest that humans, unlike mice, do not produce a strong immune response to DNA-based cancer vaccines.
In previous work, Dow and his co-workers had established that nanoparticles formed from DNA and positively charged liposomes are potent activators of the innate immune system, which involves cells called leukocytes, natural killer cells, and mast cells, among others. The innate immune system acts as a first line of defense against infection. Activation of the innate immune system triggers the more complex adaptive immune response, which is associated with antibody production. Dow and others have also shown that such nanoparticles will trigger the release of cytokines, potent stimulators of the adaptive immune system.
In this study, the investigators showed that simply mixing the dendrimer with antisense oligodeoxynucleotides triggered a self-assembly process that generated stable nanoparticles. Electron microscopy revealed that these nanoparticles were toroidal in shape, a finding that implies that the dendrimer and oligodeoxynucleotide first zip together to form a single structure that then wrap around themselves to create the final nanoparticle.
To test the hypothesis that such nanoparticles might do a better job than conventional DNA vaccines at killing tumors, the investigators created a DNA plasmid that earlier experiments had shown will elicit some antitumor activity. They then created a lipid-based nanoparticle by mixing this plasmid with a standard cationic liposome. Mice with human colon tumors were then immunized with either the plasmid or the nanoparticle.
Within two weeks of immunization, it was clear that the nanoparticles had triggered a much stronger immune response, which was translating into a more potent antitumor effect. In addition, the investigators found that immunization with the nanoparticles increased the survival rate in animals with established lung metastases
The investigators found that they could tie this enhanced response to a boost in the production of a specific type of T cell, known as CD8(+), as well as to a boost in the production of several cytokines. More importantly, the CD8(+ )cells produced in response to nanoparticle vaccination were more active than those produced in response to vaccination with plasmid DNA. The researchers also found that nanoparticle vaccination boosted activation of the adaptive immune system.
This work, which was supported by the National Cancer Institute, is detailed in a paper titled, “Vaccination with liposome – DNA complexes elicits enhanced antitumor immunity.” An investigator from the National Jewish Medical and Research Center also participated in this study. An abstract of this paper is available through
PubMed.
Source: National Cancer Institute
Related stories:
Using magnetic nanoparticles to combat cancer
Scientists at Georgia Tech have developed a potential new treatment against cancer that attaches magnetic nanoparticles to cancer cells, allowing them to be captured and carried out of the body. The treatment, which has been tested in the laboratory and will now be looked at in survival studies, is detailed online in the
Journal of the American Chemical Society.
Researchers target tumors with tiny 'nanoworms'
Scientists at UC San Diego, UC Santa Barbara and MIT have developed nanometer-sized “nanoworms” that can cruise through the bloodstream without significant interference from the body’s immune defense system and—like tiny anti-cancer missiles—home in on tumors.
Team develops safe, effective RNA interference technique
A team of researchers from MIT and Alnylam Pharmaceuticals has developed safe and effective methods to perform RNA interference, a therapy that holds great promise for treating a variety of diseases including cancer and hepatitis.
New Nanoparticles for Targeting Tumors
As a wide variety of nanoparticles continue to demonstrate their ability to improve the delivery of imaging agents and drugs to tumors, nanoparticle researchers have turned their attention to the challenge of systematically determining how a given nanoparticle’s physical and chemical characteristics affect its ability to target tumors. Such data could provide drug developers with guidelines to help them select the most effective type of nanoparticle for a given therapeutic or imaging application.
Scientists may have identified new target for HIV vaccine
By coaxing the HIV-1 protein to reveal a hidden portion of its protein coat, scientists at Dana-Farber Cancer Institute and Harvard Medical School have provided a newly detailed picture of how protective, or so-called broadly neutralizing, antibodies block HIV-1 infection.
New picture of HIV-1's protein jacket identifies target for antibody-based vaccine
By coaxing the HIV-1 protein to reveal a hidden portion of its protein coat, scientists at Dana-Farber Cancer Institute and Harvard Medical School have provided a newly detailed picture of how protective, or so-called broadly neutralizing, antibodies block HIV-1 infection.
Gold nanorods shed light on new approach to fighting cancer
Researchers have shown how tiny "nanorods" of gold can be triggered by a laser beam to blast holes in the membranes of tumor cells, setting in motion a complex biochemical mechanism that leads to a tumor cell's self-destruction.
New nanoparticle vaccine is more effective but less expensive
Good news for public health: Bioengineering researchers from the EPFL in Lausanne, Switzerland, have developed and patented a nanoparticle that can deliver vaccines more effectively, with fewer side effects, and at a fraction of the cost of current vaccine technologies.