Annual Report - 2005-2006
Tiny Particles Pack
By Scott Merville
Nanoparticles — molecules so small that they are measured in billionths of a meter — have a talent for gathering inside tumors.
After slipping through large pores in leaky blood vessels that nourish tumors, these tiny materials can be taken up into the cancer cells. Their potential to destroy tumors is being tested by M. D. Anderson researchers, who are investigating the use of nanoparticles to deliver therapy, imaging agents or both.
“Nanoparticles can be used for both therapy and diagnostics,” says Chun Li, Ph.D., professor in the Department of Experimental Diagnostic Imaging. Combining the two functions in one nanoparticle would allow “you to watch where the therapy goes and monitor the treatment in real time.” Li is developing such a particle.
With a $2.5 million, five-year National Cancer Institute Nanotechnology Platform Partnerships program grant, Li also is working with Eastman Kodak to develop nanoparticles that bind to tumors and light up under near-infrared light. Near-infrared
fluorescence-based optical imaging is sensitive, involves no ionizing radiation and allows real-time visualization, he says.
Li has connected molecules of the drug paclitaxel to a nano-sized, water-soluble polymer, which appears to heighten the chemotherapy’s effect. Polymers are molecules that consist of repeated structural units. That combination is being tested in a Phase III lung cancer clinical trial sponsored by Cell Therapeutics, Inc.
Nanoparticles, researchers say, will work best with a targeting component that binds to cancer cells and avoids normal tissue.
Hitching a ride
Michael Rosenblum, Ph.D., professor in the Department of Experimental Therapeutics, specializes in targeting constructs — antibodies, growth factors, peptides — that home in on cancer.
He has three drugs in development, which combine a targeting component with a cancer toxin. One is being evaluated in a Phase I clinical trial. While these fusion proteins are not nanoparticles, Rosenblum is collaborating with colleagues from Rice University to examine the potential role of fullerenes in a fusion approach. Also called buckyballs, fullerenes are nanospheres of 60 carbon atoms.
The researchers reported last year that buckyballs can carry chemotherapeutic agents such as Taxol. They also showed a single antibody that targets skin cancer is capable of carrying up to 40 buckyballs, which did not hinder the antibody’s cancer-targeting ability. The findings raise the possibility of developing powerful, tightly targeted therapeutics by attaching buckyballs loaded with drugs to an antibody or other targeting molecule, Rosenblum says.
As good as gold
With its low toxicity and well-known optical, biological and biodistribution properties, gold is an attractive nanomaterial, says John D. Hazle, Ph.D., chair of the Department of Imaging Physics.
Hazle collaborates with researchers at Rice, who invented gold nanoshells, and Nanospectra Biosciences to exploit the unique optical properties of nanoshells in oncology. The nanoshells under investigation are spheres of silicon coated with gold. When exposed to near-infrared light, they become intensely hot and burn the tumor cells or microvasculature, Hazle says. His team is working with several groups on attaching biological entities to permit a more targeted approach.
Renata Pasqualini, Ph.D., and Wadih Arap, M.D., Ph.D., both professors of medicine in the Departments of Genitourinary Medical Oncology and Cancer Biology, are harnessing gold to viral particles, creating a “nanoshuttle” to target tumors. The viral particles are engineered to zero in on the target tissue’s vascular “zip code.” Earlier, they discovered that the human vascular system has unique molecular addresses for different organs and tissues.
In a laboratory study, they found that targeted viral and gold nanoparticles could be “tuned” to destroy tissue or emit signals detected by imaging devices. The system can be adapted to carry drugs, genes or restorative stem cells.
Buckyballs and other materials pose an additional challenge — how to get rid of them after they deliver their payload. Biodegradable nanoparticles such as liposomes or constructs made from cholesterol dissolve at delivery.
Jack Roth, M.D., delivers cancer-fighting genes to tumors by encasing them in a cholesterol formulation that binds to the membrane of cancer cells. Once inside the cell nucleus, the gene expresses a protein that kills the tumor cells, says Roth, who recently retired as chair of the Department of Thoracic and Cardiovascular Surgery.
Based on Roth’s preclinical studies, nanoparticles carrying the tumor-suppressor gene FUS1 are being delivered to patients with metastatic lung cancer in a Phase I clinical trial. “So far it looks promising with little toxicity,” Roth says. The delivery system can be engineered to meet the characteristics of a patient’s tumor.
Roth also is collaborating to develop “theranostic” nanoparticles that deliver therapeutic and diagnostic agents.
Nanoparticles also can be used to silence cancer-promoting genes.
Gabriel Lopez-Berestein, M.D., professor in the Department of Experimental Therapeutics, and Anil K. Sood, M.D., professor in the Departments of Gynecologic Oncology and Cancer Biology, employ a fatty sphere called a liposome to deliver short interfering RNA (siRNA) directly and deeply into cancer cells. RNA translates genetic information into proteins. Targeted siRNA can gum up RNA, preventing creation of a harmful protein.
In preclinical studies, their siRNA liposome turned off a gene critical to ovarian tumor growth and decreased new blood vessel development. The best effect was seen when combined with chemotherapy. They hope to see equally positive results in the clinic.
Lopez-Berestein and Sood collaborate with Mauro Ferrari, Ph.D., in early research of multiple-stage nanoparticles. “Each stage of the multi-layered particle would be equipped with a different therapy to overcome barriers that any drug faces in the body,” says Ferrari, who holds a joint appointment at The University of Texas Health Science Center at Houston and M. D. Anderson and is president of Houston’s Alliance for NanoHealth.
The Alliance for NanoHealth awarded $2 million in seed grants for research projects in 2006. M. D. Anderson researchers lead four of the 10 diverse projects.
While nanotechnology remains a work in progress, Lopez-Berestein is encouraged by the varied approaches. “Scientists are trying everything to make effective nanoparticles.”