A new hydrogel-based drug delivery system enhances the cancer-fighting activity of doxorubicin by balancing the acidic environment in a tumor. The chitosan-poly(ethylene glycol) hydrogel system, which is injectable, directly delivers the drug to malignant tumors, helping to reduce unwanted side effects that occur when the drug isn’t released directly in the targeted site.

The hydrogel is designed to balance pH levels in a malignant tumor. More specifically, it is dual-loaded with doxorubicin and sodium bicarbonate which provides “alkaline buffering of extracellular acidity and simultaneous chemotherapeutic delivery to increase chemotherapeutic efficacy.”

The researchers say the hydrogel has the potential to substantially improve chemotherapeutic treatments and reduce the risk of aggressive cancers spreading in the body by neutralizing acid levels in tumors.

The research is described in the paper, “Increasing Chemotherapeutic Efficacy Using pH-Modulating and Doxorubicin-Releasing Injectable Chitosan-Poly(ethylene glycol) Hydrogels,” which was recently published in ACS Applied Materials and Interfaces.

“At its core, the research is about mitigating some of the critical problems that we face in cancer treatment,” said Zahra Ahmed, a graduate student in the lab of Vikas Srivastava, PhD, assistant professor of engineering at Brown University.

In the tumor microenvironment, many factors can negatively impact patient prognosis and chemotherapeutic efficacy. One of the main problems is acidosis of the tumor environment. In patients, this increases the likelihood of metastasis and reduces the effectiveness of chemotherapeutics.

In acidic environments, doxorubicin—one of the current leading chemotherapeutics—goes through ion trapping where the drug gets trapped by the acidic environment outside the cells. Because it can’t penetrate inside the cells, it cannot kill them.

Doxorubicin is toxic when administered through intravenous delivery. In addition, there is no current method to directly balance acidic pH levels in cancerous tumors.

“What we’re trying to do is to develop a method to locally deliver doxorubicin but also mitigate acidosis at the same time,” Ahmed said. “To do this, we created an injectable hydrogel where we combined the delivery of the chemotherapeutic doxorubicin with something to combat the acidic pH in the local region. In this case, we used sodium bicarbonate, a chemical compound that is commonly used to treat acid indigestion.”

Initial experiments on breast cancer cells in vitro show efficacy of the method. The hydrogel acts as a buffer and uses the sodium bicarbonate to increase the pH level, which causes the chemotherapeutic power of doxorubicin in killing the cancer cells to increase by a factor of two to three.

“When we had success in pH regulation using hydrogels, which has been shown to reduce metastasis in certain cancers, we then began figuring out how to get a sodium bicarbonate delivery system to a precise tumor location,” said Srivastava. “We formulated an injectable hydrogel that can be locally delivered and has the ability to regulate the pH of the tumor environment. We then wondered if we could also simultaneously deliver a chemotherapeutic. Can we deliver doxorubicin locally using the same delivery vehicle? We’ve now done all these things together to a great effect and have shown very promising results on two cancer cell lines in vitro.”

The researchers chose to develop a biocompatible hydrogel as their delivery system because of their growing use and versatility. Hydrogels, for example, are used for manufacturing contact lenses, hygiene products, and used for drug release and medical dressings. The hydrogel system can be stored at 4 degrees Celsius for long terms of time before use.

Next, the team hopes to apply its combined pH regulating and therapeutic delivering hydrogel system in preclinical settings and go from experiments in test tubes to experiments in animals and eventually progress to human patients.

The hydrogel system acts as a buffer to the drug doxorubicin and delivery system, helping reduce unwanted side effects and has the potential to improve chemotherapeutic treatments. [Srivastava Lab/Brown University]
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