Magnetic Nanoworms and Nanocrystals Deliver siRNA to Tumors

Sep 23, 2009

(PhysOrg.com) -- Small pieces of nucleic acid known as short interfering RNAs, or siRNAs, can turn off the production of specific proteins, a property that makes them one of the more promising new classes of anticancer drugs in development. Indeed, at least two siRNA-based anticancer therapies, both delivered to tumors in nanoparticles, have begun human clinical trials.

Now, investigators at the Massachusetts Institute of Technology (MIT) have developed a modular nanoparticle-based that maximizes the quantity of siRNA molecules that not only can enter cells but also can escape into the cytoplasm, where they can interfere with protein production. Sangeeta Bhatia, M.D., Ph.D., and Phillip A. Sharp, Ph.D., of the MIT-Harvard Center of Nanotechnology Excellence, and Alain Charest, Ph.D., M.Sc., Tufts University School of Medicine, led the study, whose results appear in the journal ACS Nano.

The new siRNA delivery vehicle is made of dendrimer-conjugated magnetic and fluorescent nanoworms that the investigators call “dendriworms.” Dendrimers are synthetic polymers that generally have a spherical shape and that can be readily modified to carry a wide range of molecules, including nucleic acids. In this work, Dr. Bhatia and her colleagues used polyamidoamine dendrimers, which a large body of preclinical work has shown are fully biocompatible, and coupled them to a chain of magnetic nanoparticles known as a nanoworm. The investigators also added a fluorescent molecule to the nanoworms, thereby creating a drug delivery vehicle that they could also image in the body using either or fluorescence imaging. In a final step, the researchers added siRNA to the dendriworms. The resulting construct, which contains approximately 7 magnetic nanoparticles, 45-50 dendrimers, and 50 siRNA molecules, was stable under test conditions for up to 6 hours.

When added to cells growing in culture, this siRNA-dendrimer complex rapidly entered the cells and then escaped into the cellular cytoplasm. The researchers observed no significant toxicity in these in vitro experiments. When the dendriworms were administered to human glioblastoma cells, the delivered siRNA was able to silence production of the targeted gene, in this case a mutant gene known to be involved in glioblastoma development.

To test whether this dendriworm would work in a living animal, the researchers used a strain of mice that were genetically engineered to develop glioblastoma tumors spontaneously in the brain. The investigators found that the dendriworms were able to penetrate the tumors, deliver their therapeutic siRNA cargo into tumor cells, and silence the targeted gene in those cells.

Meanwhile, a group of investigators at The Jikei University School of Medicine in Tokyo, Japan, led by Yoshihisa Namiki, M.D., has demonstrated that lipid-coated magnetic crystals can safely and effectively deliver therapeutic siRNA to tumors in mice. The results of their experiments were published in the journal Nature Nanotechnology.

Dr. Namiki and his colleagues created their delivery vehicle by coating iron oxide nanocrystals with a layer of positively charged lipids. This layer binds strongly to siRNA molecules, which— like all —have a strong negative charge. After optimizing the lipid coating to maximize siRNA delivery efficiency, the investigators used their nanoparticle to deliver an anti-EGFR siRNA to gastric tumors in mice. After injecting the mice with the therapeutic nanoparticles, the investigators applied a local magnetic field around the vicinity of the . After 28 days, tumors in the treated mice were 50% smaller compared with tumors in mice treated with just the nanoparticle and no siRNA.

The work with dendriworms, which is detailed in the paper “Functional delivery of siRNA in mice using dendriworms,” was supported by the NCI Alliance for Nanotechnology in Cancer, a comprehensive initiative designed to accelerate the application of nanotechnology to the prevention, diagnosis, and treatment of cancer. Investigators from Brigham and Women’s Hospital also participated in this study. An abstract is available at the journal’s Web site.

The work on magnetically guided siRNA therapy is detailed in the paper “A novel magnetic crystal-lipid nanostructure for magnetically guided in vivo gene delivery.” An abstract of this paper is available at the journal’s Web site.

Provided by National Cancer Institute (news : web)

Explore further: Research reveals how our bodies keep unwelcome visitors out of cell nuclei

add to favorites email to friend print save as pdf

Related Stories

Pack 'Em In -- Gold Nanoparticles Improve Gene Regulation

Feb 23, 2009

Investigators at Northwestern University have found that packing small interfering RNA (siRNA) molecules onto the surface of a gold nanoparticle can protect siRNAs from degradation and increase their ability to regulate genes ...

Nanoparticles Image Breast Cancer

Jul 21, 2009

Current methods of detecting breast cancer suffer from low sensitivity, limited spatial resolution, or the need to use complicated and expensive radioisotope-based technologies. A new report from investigators at the Emory-Georgia ...

Nanoparticles Delivery of 'Suicide DNA' Kills Prostate Tumors

May 22, 2007

Using nanoparticles developed by members of the Alliance for Nanotechnology in Cancer, a team of investigators at the Lankenau Institute for Medical Research, in Philadelphia, has developed a DNA-based therapeutic agent that ...

Scientists improve delivery of cancer-fighting molecules

Aug 27, 2009

Small interfering RNA (siRNA), a type of genetic material, can block potentially harmful activity in cells, such as tumor cell growth. But delivering siRNA successfully to specific cells without adversely ...

Recommended for you

A gut reaction

Nov 19, 2014

Queen's University biologist Virginia Walker and Queen's SARC Awarded Postdoctoral Fellow Pranab Das have shown nanosilver, which is often added to water purification units, can upset your gut. The discovery ...

User comments : 0

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.