January 13, 2015
- Researchers compared the amount of doxorubicin and its nanoparticle counterpart, Doxil, delivered to two tumor models of triple-negative breast cancer.
- Both tumors received much more Doxil than doxorubicin, which was expected. But one type of tumor received twice as much Doxil as the other, surprising the researchers.
- Doxil is a drug made up of nanoparticles that contain approximately 10,000 of molecules of doxorubicin.
Nanoparticle drugs—tiny containers packed with medicine and with the potential to be shipped straight to tumors—were thought to be a possible silver bullet against cancer. However, new cancer drugs based on nanoparticles have not improved overall survival rates for cancer patients very much.
Scientists at the University of North Carolina at Chapel Hill think that failure may have less to do with the drugs and tumors than it does the tumor’s immediate surroundings. The abnormal infrastructure tumors build around themselves creates barriers that may interfere with the delivery of relatively large nanoparticles.
Clinicians may need to learn more about a patient’s tumor before prescribing treatment with one of the newer nanoparticle drugs, says William Zamboni, PharmD, PhD, the study’s senior author and an associate professor at the UNC Eshelman School of Pharmacy.
Great Balls of Meds
“The idea that the tumor microenvironment might affect the delivery of drugs to tumors is a relatively new theory,” Zamboni says. “Our study is the first to report on factors that are affecting the delivery of nano agents but do not affect standard small-molecule agents.”
Zamboni and colleagues from the UNC Lineberger Comprehensive Cancer Center and the UNC School of Medicine joined forces to see how much of the cancer drug doxorubicin and its nanoparticle version, Doxil, actually made it into two types of breast-cancer tumors.
Like most drugs, doxorubicin is a small-molecule drugs that breaks down into a flood of individual molecules that spread throughout the body. Some molecules reach cancer cells; others go elsewhere and cause many of the unpleasant side effects of chemotherapy.
Doxil carries approximately 10,000 molecules of doxorubicin in a liposome, a bubble about a 100 nanometers across made of a fatty material similar to a cell membrane. These bubbles have the innate ability to home in on tumors while avoiding normal cells.
A Tale of Two Tumors
The researchers treated two varieties of triple-negative breast-cancer tumors models using both doxorubicin and Doxil. The team then looked at how much of each drug made it into each type of tumor model, known as C3-TAg and T11. The models were created by Chuck Perou, PhD, the May Goldman Shaw Distinguished Professor of Molecular Oncology at the UNC School of Medicine and a professor at UNC Lineberger.
Triple-negative breast cancer accounts for 10 to 17 percent of cases and has a poorer prognosis overall than other types of breast cancer.
“We saw that significantly more of the nanodrug Doxil made it into both types of tumor than did doxorubicin. That’s nothing new: it’s the same thing we’ve seen twenty years,” Zamboni says. “We also saw the same amount of doxorubicin in both tumors. Again, no surprise there.”
What did surprised the researchers, Zamboni say, was that twice as much Doxil was delivered to the C3-TAg tumor than to the T11 tumor.
“These tumors are subtypes of a subtype of one kind of cancer and are fairly closely related,” Zamboni says. “If the differences in delivering nano agents to these two tumors are so significant, we can only imagine what the differences might be between breast cancer and lung cancer.”
Drugs in the Hood
The researchers theorize that the tumor’s immediate surroundings, or microenvironment, may affect nanoparticles while small molecules slip through unimpeded. It’s also possible that the microenvironment is affected by the nanoparticle drug.
“Tumors create bad neighborhoods,” Zamboni says. “They spawn leaky, jumbled blood vessels that are like broken streets, blind alleys, and busted sewers. There are vacant lots densely overgrown with collagen fibers. Immune-system cells patrolling the streets could be good guys turned bad actually working for the tumor. And we’re trying to get a large truckload of medicine through all of that.”
- Nanoparticles tend to be swept up by scavenger blood cells called macrophages that can be called to the area by signaling molecules released by the tumor.
- Collagen fibers that normally form the framework for the body’s tissues can grow unchecked and form dense thickets.
- Tumors spawn a maze of new blood vessels to feed themselves. This leaky, incomplete network can provide a way in for nanoparticle drugs, but it can also result in an unintended exit. There might be a sweet spot with the abnormal blood vessels—not too many or not too few — that allows nanoparticles to enter tumors, Zamboni says.
Know Your Target
The study’s authors suggest that better profiling of tumors and their microenvironments would allow doctors to better identify patients who would most benefit from nanoparticle-based cancer therapies. Their findings are published in Clinical Cancer Research.
“The factors that alter drug delivery vary from person to person, from cancer to cancer, and even from tumor to tumor,” Zamboni says.
The Study Authors
- Gina Song, PharmD, PhD, is a former graduate student in the Division of Pharmacotherapy and Experimental Therapeutics at the UNC Eshelman School of Pharmacy.
- David B. Darr is assistant director for shared resources at the UNC Lineberger Comprehensive Cancer Center and director of Mouse Phase Unit 1 at the UNC School of Medicine.
- Charlene M. Santos is facility director of the Animal Studies Core in the UNC Lineberger Comprehensive Cancer Center.
- Mark Ross is a research technician in the Animal Studies Core in the UNC Lineberger Comprehensive Cancer Center.
- Alain Valdivia is a research specialist at the Animal Studies Core in the UNC Lineberger Comprehensive Cancer Center.
- Jamie L. Jordan, UNC Lineberger Comprehensive Cancer Center (student?)
- Bentley R. Midkiff, Translational Pathology Lab in the UNC School of Medicine.
- Stephanie Cohen, Translational Pathology Lab in the UNC School of Medicine.
- Nana Nikolaishvili-Feinberg, PhD, is facility director of the Translational Pathology Lab in the UNC School of Medicine.
- C. Ryan Miller, MD, PhD, is an assistant professor in the Department of Pathology and Laboratory Medicine, director of the Translational Pathology Lab, and a member of the UNC Lineberger Comprehensive Cancer Center.
- Teresa K. Tarrant, MD, is an associate professor in the Department of Medicine, Division of Rheumatology, Allergy, and Immunology and a member of the Thurston Arthritis Research Center and Lineberger Comprehensive Cancer Center.
- Arlin B. Rogers, DVM, PhD, associate professor and head of the section of pathology at the Tufts University Cummings School of Veterinary Medicine.
- Andrew C. Dudley, PhD, is an assistant professor in the Department of Cell and Molecular Physiology and a member of the Lineberger Comprehensive Cancer Center.
- Charles M. Perou, PhD, is the May Goldman Shaw Distinguished Professor of Molecular Oncology in the UNC School of Medicine and a member of the Lineberger Comprehensive Cancer Center.
- William C. Zamboni, PharmD, PhD, is an associate professor in the Division of Pharmacotherapy and Experimental Therapeutics at the UNC Eshelman School of Pharmacy. He is a member of the School’s Center for Pharmacogenomics and Individualized Therapy and Carolina Center of Cancer Nanotechnology Excellence. He is a member of the Lineberger Comprehensive Cancer Center.
This study was supported by the NIH Clinical and Translational Science Award (Award Number UL1RR025747) from the National Center for Research Resources, by the Carolina Center for Cancer Nanotechnology Excellence (CCCNE; 1 U54 CA151652) from the NCI, and by the UNC Lineberger Comprehensive Cancer Center Cancer Center Support Grant (P30 CA016086) from the NCI.