Delving into the world of the extremely small, researchers from The Children’s Hospital of Philadelphia are exploring how biodegradable nanoparticles can precisely deliver anticancer drugs to attack neuroblastoma, an often-deadly children’s cancer.
By bringing together experts in pediatric oncology with experts in nanotechnology, Children’s Hospital investigators aim to thread the needle of delivering effective doses of cancer-killing agents while avoiding toxicity in healthy tissues. The team’s new research shows that this approach inhibits tumor growth and markedly prolongs survival in animal models.
“These nanoparticles allow us to get more ‘bang for the buck’— greater efficacy at lower total doses,” said CHOP’s Garrett M. Brodeur, MD, a pediatric oncologist and expert in neuroblastoma. “The nanoparticles are designed to slowly deliver a drug to the tumor, where it kills multiplying cancer cells, with lower toxicity to the systemic circulation.”
Dr. Brodeur’s group collaborated with a group of CHOP nanotechnology researchers led by Michael Chorny, PhD, in a study published in Cancer Letters. In turn, Dr. Chorny led a study to be published in the May print issue of Biomaterials, in collaboration with Brodeur’s group and with Robert Levy, MD, and Ivan Alferiev, PhD, both members with Dr. Chorny of a cardiology research group at CHOP. That paper described how the team engineered the specially formulated nanoparticles.
Drs. Brodeur and Chorny’s work was previously highlighted in the 2014 Research Annual Report. Nanoparticles’ biodegradability means that they won’t linger in patients’ bodies long after delivering their payloads. “They are simple molecules that are fairly easy and inexpensive to make,” said Dr. Brodeur. “
They are very effective at doing their job, and then they just break down.”
Exploiting Neuroblastoma Tumors’ Vulnerability
Using nanoparticles to deliver treatments, explained Dr. Brodeur, exploits one vulnerability of tumors: the EPR, or enhanced permeability and retention, effect. “In healthy tissue there are tight junctions in blood vessels,” said Dr. Brodeur. “But tumors don’t have those tight junctions and have inefficient circulation, so the nanoparticles we deliver bypass healthy tissues, but accumulate in tumors where they release the anticancer agents.”
Neuroblastoma is a solid tumor of the peripheral nervous system, often appearing in a child’s abdomen or chest. The most common cancer in infants, neuroblastoma accounts for a disproportionate share of cancer deaths in children, with cure rates lagging behind those for most other pediatric cancers.
“In pediatric oncology, we have largely relied on drugs developed 30 to 40 years ago,” said Dr. Brodeur. “While these have greatly improved overall cure rates over that period from 20 percent to 80 percent, we still need better drugs and more targeted approaches for the most stubborn childhood cancers, including high-risk forms of neuroblastoma.’
Drs. Brodeur, Chorny, and colleagues used their nanoparticle formulations to deliver a precursor of SN38, the active form of irinotecan, a conventional anticancer drug used for the past 20 years against relapsed neuroblastoma. In laboratory mice, the study team compared results obtained with the nanoparticle-encapsulated SN38 to those using a comparable dose of irinotecan.
The injected nanoparticles delivered SN38 to the tumor in amounts 100-fold higher than irinotecan, with sustained drug presence over at least 72 hours, and no evidence of toxicity in the mice. In addition, most of the mice survived tumor-free for over 6 months after nanoparticle delivery, whereas all the mice treated with irinotecan had tumor recurrence shortly after treatment stopped, and they all died shortly after.
The nanoparticles in the study are ultrasmall, less than 100 nanometers in diameter (a nanometer is one-millionth of a millimeter, much tinier than red blood cells).
Dr. Brodeur aims to translate these preclinical results to human trials within the next year. He added that if nanoparticle delivery proves its worth in clinical trials, it may join three other molecularly-targeted innovations in pediatric cancer treatment already available at CHOP: immunotherapy using bioengineered T cells, radioactive isotopes that preferentially bind to cancer cells, and kinase inhibitors that interrupt abnormal signaling triggered by cancer-driving mutations.
Some nanoparticles are already being used to treat adult cancers, but if the current technique achieves clinical success in neuroblastoma, it would markedly strengthen the arsenal of approaches currently available for treating a childhood cancer. It holds the potential for broader applications as well, such as delivering other drugs and treating other cancers currently treated with irinotecan, perhaps even those that are currently considered resistant to this drug. For more information about the Cancer Letters and Biomaterials studies, see the full press release. And for a sample of the groundbreaking research conducted at CHOP Research every day, see the 2014 Research Annual Report.