Targeting Drugs to Pancreatic Cancer Through Implantable Device
Therapy delivered locally by an implantable device suppressed the growth of pancreatic cancer 12-fold more than therapy systemically administered intravenously, according to preclinical research done in mouse models.1
Part of the reason pancreatic cancer is the third-leading cause of cancer death in the United States is because it is very difficult for chemotherapy drugs to reach the pancreas. The 5-year overall survival rate for pancreatic cancer is below 6%. Pancreatic tumors are hard to treat because the pancreas is so deep within the body, the tumors have few blood vessels, and the tumors are often surrounded by a thick, fibrous coating that keeps drugs out.
A small, implantable device that delivers chemotherapy drugs directly to pancreatic tumors was developed to address the challenging location of the pancreas.
"It's clear there is huge potential for a device that can localize treatment at the disease site," said lead author Laura Indolfi, PhD, a postdoc in the Massachusetts Institute of Technology's Institute for Medical Engineering and Science (IMES) and the Massachusetts General Hospital Cancer Center. She is also CEO of PanTher Therapeutics, which was formed to commercialize the device. "You can implant our device to achieve a localized drug release to control tumor progression and potentially shrink [the tumor] to a size where a surgeon can remove it."
The researchers explained that this thin, flexible film could also be adapted to treat other hard-to-reach tumors. The flexible film is made from the polymer PLGA, which is widely used for drug delivery and other medical applications. The film can be rolled into a narrow tube and inserted through a catheter, so surgically implanting it is relatively simple. Once the film reaches the pancreas, it unfolds and conforms to the shape of the tumor.
"Because it is very flexible it can adapt to whatever size and shape the tumor will have," Dr Indolfi said.
Drugs are embedded into the film and then released over a preprogrammed period of time. The film is designed so that the drug is only secreted from the side in contact with the tumor, minimizing side effects on nearby organs.
For this study, 2 groups of mice with transplanted human pancreatic tumors were compared. The drug-delivery implant loaded with the chemotherapy drug paclitaxel was delivered to 1 group, while the other received systemic injections of the same drug for 4 weeks, to mimic the treatment human patients usually receive.
In mice with the drug-delivery implant, tumor growth slowed, and in some cases tumors shrank. The localized treatment also increased the amount of necrotic tissue (dead cancer cells that are easier to remove surgically). Additionally, by acting as a physical barrier, the film was able to reduce metastasis to nearby organs.
After 4 weeks, the mice with the implanted device had a 5-fold higher concentration of paclitaxel in their tumors than did the mice that received injections. The lack of blood vessels in pancreatic tumors probably helped the drug to stay in the pancreas and not spread to nearby organs, so toxic effects in healthy tissues were prevented.
The researchers are now preparing to design a clinical trial for human patients. While they began this project with a focus on pancreatic cancer, they expect that this approach could also be useful in treating other tumors that are difficult to reach, such as tumors of the gastrointestinal tract.
"The greatest benefit of this device is the ability to implant it with minimally invasive procedures so we can give a tool to oncologists and surgeons to reach tumors that otherwise would be difficult to reach," Dr Indolfi said. Further, the novel delivery platform may allow the development of the many promising anticancer agents that had encouraging preclinical data but had systemic dose-limiting toxicities that meant they could not be used in patients.
1. Indolfi L, Ligorio M, Ting DT, et al. A tunable delivery platform to provide local chemotherapy for pancreatic ductal adenocarcinoma. Biomaterials. 2016; 93:71-82. doi:10.1016/j.biomaterials.2016.03.044.