Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

RNAi delivery system crosses blood-brain barrier to target brain cancer

01.06.2004


Researchers have combined novel molecular targeting technologies to deliver gene-silencing therapy specifically to tumor cells shielded by a normally impermeable obstacle, the blood brain barrier.



In the June 1 issue of the journal Clinical Cancer Research, William Pardridge, M.D., UCLA, reported that a delivery packet equipped with two specific antibodies first recognizes the transferrin receptor, a key protein portal in the blood brain barrier, and then gains entry into brain cancer cells with the second antibody targeting the human insulin receptor.

Using the antibody keys to traverse both the blood brain barrier and the tumor cell membrane, the delivery packets--called liposomes--deposit a genetically engineered non-viral plasmid in the brain cancer cells. The plasmid encodes a short hairpin RNA (shRNA) designed to interfere with the expression of the epidermal growth factor receptor, EGFR, a potent proponent of tumor cell proliferation. The use of shRNA to silence gene expression is RNA interference (RNAi) technology.


When treated with a weekly intravenous dose of Dr. Pardridge’s targeted therapeutic, mice with brain tumors survive almost twice as long compared to mice that do not receive the treatment.

"This is the first drug delivery system that demonstrates that by using RNA interference technology, you can prolong life threatened by cancer," said Dr. Pardridge, Professor of Medicine at UCLA. "By solving the delivery problem, powerful molecular tools and therapies such as RNA interference can be moved to clinical trials where they can be tested to see how much benefit the patient gets."

The delivery system designed by the Pardridge research team is much like a minute parcel with a primary delivery address, a forwarding delivery address, and a message that halts proliferation of the tumor cells.

Liposomes are the parcel. Composed of lipid, or fat, molecules that align to form an enclosed membrane much like a sealed envelope, the liposomes are constructed with thousands of molecular probes that recognize two specific proteins. The proteins are the addresses to which the liposome is targeted. One antibody that is engineered into the liposome recognizes only the transferrin receptor, a protein common to the blood brain barrier. By binding tightly to the transferrin receptor, the liposome gains entry to the chamber in which the brain is normally screened from pathogens, foreign proteins, and even small molecules.

Once inside the compartment that houses and protects the brain, a second set of liposome-embedded antibodies seeks out the human insulin receptor found in the membranes of brain cancer cells. The insulin receptor antibody latches on to the tumor’s insulin receptors. The liposome, and its contents, uses the insulin receptor to gain entry to the tumor cell.

Within the tumor cell, the plasmid payload is released from the liposome.

"This is the ’Trojan Horse’ element of the therapy," Dr. Pardridge said. The liposome acts as the hollowed horse; the plasmid is the Trojan warrior released inside the cell to combat the cancer.

The plasmid is constructed of genetic material designed to reproduce shRNA, which is then metabolized by a protein in the tumor cell called Dicer. Dicer produces the active RNAi molecule that complements a defined sequence from the EGFR gene RNA. When the tumor cell divides, the RNAi molecule is produced and binds to the message from the tumor cells’ pool of EGFR RNA. Binding of the RNAi therapeutic molecule to the cells’ innate RNA results in the silencing of the EGFR message. No EGFR protein is produced, and the gene is effectively inactivated.

Without its normal workload of EGFR proteins to encourage cell proliferation, the tumor growth is held in check.

The Pardridge group confirmed that the treatment strategy thwarted EGFR function in two ways. The EGFR is set into action when it binds a growth factor related to epidermal growth factor, a hormone growth factor that travels outside of cells in the blood. Activated EGFR normally induces a flow of calcium across tumor cell membranes. That calcium mobilization was minimized in the brain cancer cells treated with the targeted liposome packet.

Furthermore, activated EGFR induces DNA replication and cell proliferation. A radiolabeled DNA component, tritiated thymidine, is incorporated into newly synthesized DNA. By monitoring the level of radiation in the brain cancer cells, Dr. Pardridge noted minimized DNA replication, and hence, cellular proliferation, in the cancer cells that were treated with the immunoliposomes. Tumors in the treated mice had reduced EGFR content, and the mice showed an 88 percent increase in survival time.

The research leading to the Pardridge group’s design of a tandem-probed immunoliposome laden with RNAi technology was supported with funding from the Accelerated Brain Cancer Cure (ABC2), and the U.S. Government. ABC2 is a nonprofit foundation dedicated to discovery of research leading to cures for brain cancer. ABC2 was created by the late Dan Case, chairman of H.P. Morgan H&Q, and his brother Steve Case, the founder of AOL and the former chairman of AOL Time Warner.


Founded in 1907, the American Association for Cancer Research is a professional society of more than 22,000 laboratory, translational, and clinical scientists engaged in all areas of cancer research in the United States and in more than 60 other countries. AACR’s mission is to accelerate the prevention and cure of cancer through research, education, communication, and advocacy. Its principal activities include the publication of five major peer-reviewed scientific journals: Cancer Research; Clinical Cancer Research; Molecular Cancer Therapeutics; Molecular Cancer Research; and Cancer Epidemiology, Biomarkers & Prevention. AACR’s Annual Meetings attract more than 15,000 participants who share new and significant discoveries in the cancer field. Specialty meetings, held throughout the year, focus on the latest developments in all areas of cancer research.

Russell Vanderboom | EurekAlert!
Further information:
http://www.aacr.org/

More articles from Health and Medicine:

nachricht Collagen nanofibrils in mammalian tissues get stronger with exercise
14.12.2018 | University of Illinois College of Engineering

nachricht New discoveries predict ability to forecast dementia from single molecule
12.12.2018 | UT Southwestern Medical Center

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Data use draining your battery? Tiny device to speed up memory while also saving power

The more objects we make "smart," from watches to entire buildings, the greater the need for these devices to store and retrieve massive amounts of data quickly without consuming too much power.

Millions of new memory cells could be part of a computer chip and provide that speed and energy savings, thanks to the discovery of a previously unobserved...

Im Focus: An energy-efficient way to stay warm: Sew high-tech heating patches to your clothes

Personal patches could reduce energy waste in buildings, Rutgers-led study says

What if, instead of turning up the thermostat, you could warm up with high-tech, flexible patches sewn into your clothes - while significantly reducing your...

Im Focus: Lethal combination: Drug cocktail turns off the juice to cancer cells

A widely used diabetes medication combined with an antihypertensive drug specifically inhibits tumor growth – this was discovered by researchers from the University of Basel’s Biozentrum two years ago. In a follow-up study, recently published in “Cell Reports”, the scientists report that this drug cocktail induces cancer cell death by switching off their energy supply.

The widely used anti-diabetes drug metformin not only reduces blood sugar but also has an anti-cancer effect. However, the metformin dose commonly used in the...

Im Focus: New Foldable Drone Flies through Narrow Holes in Rescue Missions

A research team from the University of Zurich has developed a new drone that can retract its propeller arms in flight and make itself small to fit through narrow gaps and holes. This is particularly useful when searching for victims of natural disasters.

Inspecting a damaged building after an earthquake or during a fire is exactly the kind of job that human rescuers would like drones to do for them. A flying...

Im Focus: Topological material switched off and on for the first time

Key advance for future topological transistors

Over the last decade, there has been much excitement about the discovery, recognised by the Nobel Prize in Physics only two years ago, that there are two types...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

ICTM Conference 2019: Digitization emerges as an engineering trend for turbomachinery construction

12.12.2018 | Event News

New Plastics Economy Investor Forum - Meeting Point for Innovations

10.12.2018 | Event News

EGU 2019 meeting: Media registration now open

06.12.2018 | Event News

 
Latest News

Data use draining your battery? Tiny device to speed up memory while also saving power

14.12.2018 | Power and Electrical Engineering

Tangled magnetic fields power cosmic particle accelerators

14.12.2018 | Physics and Astronomy

In search of missing worlds, Hubble finds a fast evaporating exoplanet

14.12.2018 | Physics and Astronomy

VideoLinks
Science & Research
Overview of more VideoLinks >>>