Featured Research

from universities, journals, and other organizations

Cancer therapy: Nanokey opens tumors to attack

Date:
November 14, 2012
Source:
Ludwig-Maximilians-Universität München
Summary:
There are plenty of effective anticancer agents around. The problem is that, very often, they cannot gain access to all the cells in solid tumors. A new gene delivery vehicle may provide a way of making tracks to the heart of the target.

There are plenty of effective anticancer agents around. The problem is that, very often, they cannot gain access to all the cells in solid tumors. A new gene delivery vehicle may provide a way of making tracks to the heart of the target.

Many types of tumor form a compact mass, like the phalanx formation of Greek antiquity. And although many drugs are known to be toxic to cancer cells, they are often unable to percolate into the inner recesses of the tumor. Upon intravenous administration, for instance, cytotoxic drugs may only be able to penetrate the outermost layers of a solid tumor. A team led by LMU pharmacologist Dr Manfred Ogris has now developed a new type of gene delivery vehicle, which is designed to open up a route through the vascular network that supplies the tumor so that drugs can reach their target.

Large tumors need a local blood supply for continued growth, and are capable of inducing the formation of new vessels. The resulting vasculature is more permeable than normal vessels, which should facilitate the delivery of cytotoxins. However, the lymphatic system does not work optimally in tumors, and back-pressure associated with the build-up of lymph limits the diffusion of drugs. As it happens, the cytokine Tumor Necrosis Factor α (TNFα), which can kill tumor cells directly, is able to increase blood vessel permeability as part of its pro-inflammatory function.

Shielding the organism from the drug

TNFα is already being used in combination with chemotherapeutic agents for the treatment of muscle tumors in arms and legs, but in this case, the local vasculature must be cut off surgically. "Unfortunately, therapeutically effective amounts of TNFα 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."

A new strategy employing gene therapy could provide a solution to this problem. The idea is to deliver the gene for TNFα directly and specifically to the tumor cells. If this worked, the tumor cells themselves could produce and secrete the cytokine, ensuring that its local concentration becomes sufficiently high to permeabilize the blood vessels only in the immediate vicinity of the tumor. "We first designed a version of the TNFα gene that allows for the production of large amounts of the protein," Dr. Baowei Su, first author on the study, explains.

Shielding the drug from the organism

In collaboration with researchers at the Technische Universität München and the Helmholtz Center Munich, the LMU team constructed a form of the gene which, in contrast to the normal version, is unlikely to induce non-specific inflammation. The plasmid was then incorporated into special nanoparticles, which not only protect the DNA from inactivation during its journey through the bloodstream, but also allow it to be targeted to the tumor. Experiments carried out on cell cultures confirmed that tumor cells treated with these particles synthesize large amounts of TNFα.

Treatment with the loaded nanoparticles alone, however, had only a moderate effect on tumor cells, but when they were administered in combination with the DNA-intercalating drug doxorubicin, the impact on tumor cell growth was markedly enhanced. Under the trade name Doxil, doxorubicin, which inhibits DNA replication, is available in a liposome-encapsulated form. Incorporating the drug into liposomes of 100 nm in diameter reduces side-effects and increases its half-life in the circulation, making it more effective than unencapsulated formulations.

No evidence for drug resistance

When mice with neuroblastoma, or mice that had received a xenograft of a human liver tumor, were first exposed to nanoparticles carrying the TNFα gene and subsequently treated with Doxil the researchers observed, in real time, that the drug became concentrated in the tumor tissue. Indeed, in some cases, the combination was sufficient to bring tumor growth to a standstill, even in animals that had already undergone three cycles of treatment. This finding suggests that drug resistance, which often limits the efficacy of chemotherapy, does not develop in this context.

In addition to eliminating the primary tumor, a successful therapy must be able to kill metastatic tumors in other tissues. When the researchers looked at mice with neuroblastoma, or mice carrying implanted human colon tumors that had metastasized to the liver, they found that the new treatment strategy also significantly reduced the growth of metastases. "TNFα might also be useful in combination with other agents and other treatment regimens," says Ogris. "We now plan to optimize our gene delivery system, and hope that we can soon begin to plan preclinical tests of the new approach."


Story Source:

The above story is based on materials provided by Ludwig-Maximilians-Universität München. Note: Materials may be edited for content and length.


Journal Reference:

  1. Baowei Su, Arzu Cengizeroglu, Katarina Farkasova, Joana R. Viola, Martina Anton, Joachim W. Ellwart, Rudolf Haase, Ernst Wagner, Manfred Ogris. Systemic TNFα Gene Therapy Synergizes With Liposomal Doxorubicine in the Treatment of Metastatic Cancer. Molecular Therapy, 2012 DOI: 10.1038/mt.2012.229

Cite This Page:

Ludwig-Maximilians-Universität München. "Cancer therapy: Nanokey opens tumors to attack." ScienceDaily. ScienceDaily, 14 November 2012. <www.sciencedaily.com/releases/2012/11/121114113803.htm>.
Ludwig-Maximilians-Universität München. (2012, November 14). Cancer therapy: Nanokey opens tumors to attack. ScienceDaily. Retrieved April 20, 2014 from www.sciencedaily.com/releases/2012/11/121114113803.htm
Ludwig-Maximilians-Universität München. "Cancer therapy: Nanokey opens tumors to attack." ScienceDaily. www.sciencedaily.com/releases/2012/11/121114113803.htm (accessed April 20, 2014).

Share This



More Health & Medicine News

Sunday, April 20, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Nine-Month-Old Baby Can't Open His Mouth

Nine-Month-Old Baby Can't Open His Mouth

Newsy (Apr. 19, 2014) — Nine-month-old Wyatt Scott was born with a rare disorder called congenital trismus, which prevents him from opening his mouth. Video provided by Newsy
Powered by NewsLook.com
'Holy Grail' Of Weight Loss? New Find Could Be It

'Holy Grail' Of Weight Loss? New Find Could Be It

Newsy (Apr. 18, 2014) — In a potential breakthrough for future obesity treatments, scientists have used MRI scans to pinpoint brown fat in a living adult for the first time. Video provided by Newsy
Powered by NewsLook.com
Little Progress Made In Fighting Food Poisoning, CDC Says

Little Progress Made In Fighting Food Poisoning, CDC Says

Newsy (Apr. 18, 2014) — A new report shows rates of two foodborne infections increased in the U.S. in recent years, while salmonella actually dropped 9 percent. Video provided by Newsy
Powered by NewsLook.com
Scientists Create Stem Cells From Adult Skin Cells

Scientists Create Stem Cells From Adult Skin Cells

Newsy (Apr. 17, 2014) — The breakthrough could mean a cure for some serious diseases and even the possibility of human cloning, but it's all still a way off. Video provided by Newsy
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
 
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:  

Breaking News:
from the past week

In Other News

... from NewsDaily.com

Science News

Health News

Environment News

Technology News



Save/Print:
Share:  

Free Subscriptions


Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

Get Social & Mobile


Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

Have Feedback?


Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
Mobile iPhone Android Web
Follow Facebook Twitter Google+
Subscribe RSS Feeds Email Newsletters
Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins