A new method combines an injectable radioactive gel with systemic chemotherapy to treat pancreatic cancer

A new method combines an injectable radioactive gel with systemic chemotherapy to treat pancreatic cancer

Pancreatic cancer is one of the deadliest types of cancer – in the US, it is estimated that more than 88 percent of people will die from the disease within five years of their diagnosis. One of the reasons for this dismal prognosis is that most pancreatic cancers are diagnosed after the disease has already spread or metastasized to other parts of the body. Another reason is that pancreatic cancer is particularly difficult to treat because these tumors are often resistant to standard anticancer drugs.

NIBIB-funded researchers are developing a new method of treating this deadly disease. Their study, recently published in natural biomedical engineering, combined an injectable radioactive gel with systemic chemotherapy in multiple mouse models of pancreatic cancer. The treatment led to tumor regression in all models evaluated, an unprecedented result in this genetically diverse and aggressive type of cancer.

Radiation therapy is typically delivered externally, which exposes healthy tissue to radiation and limits the dose the tumor receives, ultimately limiting its effectiveness. The radioactive biomaterial investigated in this preclinical study can be injected directly into the tumor, allowing a localized approach. What’s more, this biodegradable biomaterial allows for higher cumulative doses of radiation than other implantable radiation treatments.”

David Rampulla, Ph.D., Director of the Discovery Science & Technology Division at NIBIB

Brachytherapy – where a source of radiation is placed inside the body – can be used to treat several different types of cancer. For example, early-stage prostate cancer can be treated with “seed” brachytherapy, where many tiny metal seeds containing a radioactive substance are implanted into the prostate. While these seeds can limit the exposure of healthy tissues to radiation, their metal coating prevents the use of powerful radiation particles, known as alpha and beta emitters, which are more effective at killing cancer cells. Additionally, due to their small size, about 100 seeds are usually needed to treat prostate cancer (with each individual seed requiring an injection). To date, brachytherapy approaches have not improved clinical outcomes in patients with pancreatic cancer.

The current study investigates a new type of brachytherapy. Instead of delivering radiation using a metal seed or catheter, the study authors are investigating the use of a radioactive biopolymer that is injected directly into the tumor. In addition to being biodegradable, the biopolymer has the unique property of being designed to turn from a liquid at room temperature into a gel-like state when heated to body temperature. As the biopolymer solidifies, it remains in the tumor and cannot easily spread to surrounding healthy tissues.

“Our biopolymer is derived from elastin, an abundant protein found in connective tissues in our body,” explained first author Jeff Schaal, Ph.D., who performed the work at Duke University. “By tinkering with the composition of this biopolymer, we can control the exact temperature where it turns from a liquid to a gel. And because we’re not enclosing the radioactive polymer in a protective metal seed, we can use different and more powerful isotopes that allow us to deliver a higher dose of radiation than conventional seed brachytherapy.”

The radioactive isotope used in this proof-of-concept treatment is iodine-131 (or I-131), which releases high-energy particles known as beta particles. Beta particles cause DNA damage and kill irradiated cells, but they cannot travel very far – only a few millimeters (so off-target toxicity is limited). I-131 has been used to treat thyroid cancer for decades and has a well-established safety profile, Schaal said.

Pancreatic cancer is sometimes treated with a combination of radiation and specific chemotherapy agents that make the radiation more effective. These “radiosensitizing” drugs work by prolonging the cell’s replication process — specifically when its DNA is exposed, Schaal explained. Exposed DNA is more sensitive to radiation and more likely to be irreversibly damaged by it, ultimately leading to cell death.

Combined with a radiosensitizing chemotherapeutic known as paclitaxel, the study authors evaluated their radioactive biopolymer in several different pancreatic cancer models, carefully selected to reflect different aspects of pancreatic cancer (eg, common mutations, tumor characteristics, tumor density, or resistance to treatment). Among all the models tested, nearly every mouse responded, meaning the tumors either shrank or disappeared entirely. “The response rate we saw in our models was unprecedented,” Schaal said. “After a thorough review of the literature, we have yet to find another treatment regimen that demonstrates such a strong response in multiple and genetically diverse models of pancreatic cancer.” Furthermore, in some mice, the tumors never returned during the study.

When the study authors evaluated the current clinical treatment regimen—paclitaxel plus external beam radiation—the response rate was not nearly as impressive: the rate of tumor growth was merely inhibited, rather than the tumors shrinking or disappearing. “Unlike external beam radiation, which is delivered in short doses, our brachytherapy approach delivers radiation continuously,” explained Schaal. “We found that this continuous beta-particle radiation changed the tumor microenvironment and allowed paclitaxel to better penetrate the tumor core, allowing for a synergistic therapeutic effect.”

Importantly, the researchers observed no acute toxicity issues during their study, with negligible radioactivity accumulating in critical organs in the mice. They previously reported that their radioactive biopolymer biodegrades safely, with the gel’s half-life (roughly 95 days) far exceeding that of I-131 (roughly eight days).

The authors did not evaluate their treatment in metastatic disease, but the nature of their approach would allow biopolymer injections into multiple locations, such as tumor masses in other organs. And while this study remains in the preclinical phase, the study authors are working to move this treatment forward. “Our group is collaborating with clinical researchers to develop and optimize our system for endoscope-guided delivery in a larger animal model,” said lead author Ashutosh Chilkoti, Ph.D., a professor in the Department of Biomedical Engineering at Duke University. “However, the challenge in giving this – or any new treatment – to patients is finding the support to take it through clinical trials.”

Source:

National Institute of Biomedical Imaging and Bioengineering (NIBIB)

Link to journal:

Scale, JL, et al. (2022) Brachytherapy via biopolymer-bound 131I depot synergizes with nanoparticulate paclitaxel in therapy-resistant pancreatic tumors. Natural Biomedical Engineering. doi.org/10.1038/s41551-022-00949-4.

#method #combines #injectable #radioactive #gel #systemic #chemotherapy #treat #pancreatic #cancer

Leave a Comment

Your email address will not be published. Required fields are marked *