Features | Partner Sites | Information | LinkXpress
Sign In
GLOBETECH MEDIA
GLOBETECH PUBLISHING LLC
GLOBETECH PUBLISHING LLC

Nanoparticle Co-Delivery of a Membrane-Associated Protein and a Small-Molecule Anticancer Drug Enhanced Therapeutic Efficacy in a Mouse Model

By BiotechDaily International staff writers
Posted on 23 Jan 2014
Image: The structure of the nanoparticle (left) and how the nanoparticles home in on a tumor and shrink it (right) (Photo courtesy of North Carolina State University).
Image: The structure of the nanoparticle (left) and how the nanoparticles home in on a tumor and shrink it (right) (Photo courtesy of North Carolina State University).
Combining two anticancer drugs within a novel targeted nanoparticle overcomes their shortcomings and forms the basis for a new therapeutic agent with improved inhibition of tumor growth in a mouse xenograft- tumor model.

A team of investigators at North Carolina State University (Raleigh, USA) and the University of North Carolina (Chapel Hill, USA) sought to improve the performance of the cancer drugs doxorubicin (Dox) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL).

Although in use for more than 40 years as a primary chemotherapy drug, Dox is known to cause serious heart problems. To prevent these, doctors may limit the amount of Dox given to each patient so that the total amount a patient receives over her or his entire lifetime is 550 milligrams per square meter, or less. Furthermore, the necessity to stop treatment to protect the patient from heart disease may diminish the usefulness of Dox in treating cancer. TRAIL is a cytokine that is produced and secreted by most normal tissue cells. It causes apoptosis primarily in tumor cells by binding to certain death receptors. Since the mid-1990s, it has been used as the basis for several anticancer drugs, but has not been found to have any significant survival benefit.

To optimize the action of the two drugs, the investigators created a core and shell-based “nanodepot” consisting of a liposomal core and a crosslinked hyaluronic acid (HA)-based gel shell (designated Gelipo). Since it is a small-molecule drug intercalating the nuclear DNA, Dox was loaded in the aqueous core of the liposome. TRAIL, which acts on the death receptor (DR) on the plasma membrane, was encapsulated in the outer HA shell.

Following injection of the nanoparticles into mice carrying the MDA-MB-231 xenograft tumor, the HA shell was degraded by the hyaluronidase (HAase) enzyme that was concentrated in the tumor environment. This resulted in the rapid extracellular release of TRAIL and subsequent internalization of the liposomes, which caused release of Dox within the tumor cells.

Results published in the January 2, 2014, online edition of the journal Advanced Functional Materials revealed that the parallel activity of TRAIL and Dox showed synergistic anticancer efficacy, with the Dox-TRAIL nanoparticles being 5.9 times more effective than nanoparticles loaded only with Dox.

“In testing on laboratory mice, our technique resulted in significant improvement in breast cancer tumor reduction as compared to conventional treatment techniques,” said senior author Dr. Zhen Gu, assistant professor in the joint biomedical engineering program at North Carolina State University and the University of North Carolina.
“Cancer cells can develop resistance to chemotherapy drugs, but are less likely to develop resistance when multiple drugs are delivered simultaneously. However, different drugs target different parts of the cancer cell. For example, the protein drug TRAIL is most effective against the cell membrane, while doxorubicin (Dox) is most effective when delivered to the nucleus. We have come up with a sequential and site-specific delivery technique that first delivers TRAIL to cancer cell membranes and then penetrates the membrane to deliver Dox to the nucleus.”

“This research is our first proof of concept, and we will continue to optimize the technique to make it even more efficient,” said Dr. Gu. “The early results are very promising, and we think this could be scaled up for large-scale manufacturing.”

Related Links:

North Carolina State University
University of North Carolina



Channels

Genomics/Proteomics

view channel
Image: In mice, mitochondria (green) in healthy (left) and Mfn1-deficient heart muscle cells (center) are organized in a linear arrangement, but the organelles are enlarged and disorganized in Mfn2-deficient cells (right) (Photo courtesy of the Rockefeller Press).

Cell Biologists Find That Certain Mitochondrial Diseases Stem from Coenzyme Q10 Depletion

A team of German cell biologists has linked the development of certain mitochondrial-linked diseases to depletion of the organelles' pool of coenzyme Q10 brought about by mutation in the MFN2 gene, which... Read more

Biochemistry

view channel

Possible New Target Found for Treating Brain Inflammation

Scientists have identified an enzyme that produces a class of inflammatory lipid molecules in the brain. Abnormally high levels of these molecules appear to cause a rare inherited eurodegenerative disorder, and that disorder now may be treatable if researchers can develop suitable drug candidates that suppress this enzyme.... Read more

Lab Technologies

view channel
Image: The FLUOVIEW FVMPE-RS Gantry microscope (Photo courtesy of Olympus).

New Multiphoton Laser Scanning Microscope Configurations Expand Research Potential

Two new configurations of a state-of-the-art multiphoton laser scanning microscope extend the usefulness of the instrument for examining rapidly occurring biological events and for obtaining images from... Read more

Business

view channel

Roche Acquires Signature Diagnostics to Advance Translational Research

Roche (Basel, Switzerland) will advance translational research for next generation sequencing (NGS) diagnostics by leveraging the unique expertise of Signature Diagnostics AG (Potsdam, Germany) in biobanks and development of novel NGS diagnostic assays. Signature Diagnostics is a privately held translational oncology... Read more
 
Copyright © 2000-2015 Globetech Media. All rights reserved.