Implantable microparticles could provide two cancer treatments simultaneously

Hoping to expand treatment options for these patients, MIT researchers have developed tiny particles that can be implanted at the site of a tumor, where they provide two types of therapy: heat and chemotherapy.

This approach will avoid the side effects that often occur with intravenous chemotherapy, and the synergistic effect of the two treatments can prolong a patient’s life longer than with one treatment at a time. In a study on mice, scientists showed that this therapy completely eliminated tumors in most animals and significantly prolonged their survival.

“One example where this particular technology could be useful is in trying to control the growth of very fast-growing tumors,” says Ana Jaklenec, principal investigator at MIT’s Koch Institute for Integrative Cancer Research. “The goal is to get some control over these tumors for patients who don’t really have many options, and this could either prolong their lives or at least allow them to have a better quality of life during this period “

Jaklenec is one of the senior authors of the new study, along with Angela Belcher, the James Mason Professor of Biological Engineering and Materials Science and Engineering and a member of the Koch Institute, and Robert Langer, a professor at MIT and a member of the Koch Institute. Maria Canelli, a former MIT postdoc, is the lead author of the paper published in the journal. ACS Nano.

Dual therapy

Patients with advanced tumors usually undergo a combination of treatments, including chemotherapy, surgery and radiation therapy. Phototherapy is a new treatment that involves implanting or injecting particles that are heated by an external laser, raising their temperature enough to kill nearby tumor cells without damaging other tissue.

Current approaches to phototherapy in clinical trials use gold nanoparticles that emit heat when exposed to near-infrared light.

The MIT team wanted to come up with a way to administer phototherapy and chemotherapy at the same time, which they thought could make the treatment process easier for the patient and could also have a synergistic effect. They decided to use an inorganic material called molybdenum sulfide as a phototherapeutic agent. This material converts laser light into heat very efficiently, meaning low power lasers can be used.

To create a microparticle that could provide both of these treatments, the researchers combined molybdenum disulfide nanosheets with either doxorubicin, a hydrophilic drug, or violacein, a hydrophobic drug. To make the particles, molybdenum disulfide and a chemotherapy drug are mixed with a polymer called polycaprolactone and then dried to form a film that can be pressed into microparticles of different shapes and sizes.

For this study, the researchers created cubic particles 200 micrometers wide. Once injected into the tumor site, the particles remain there throughout treatment. During each processing cycle, an external near-infrared laser is used to heat the particles. This laser can penetrate to depths of several millimeters to centimeters, producing local effects on tissue.

“The benefit of this platform is that it can act on demand in a pulsating manner,” says Canelli. “You administer it once through an intratumoral injection, and then using an external laser source, you can activate the platform, release the drug, and at the same time achieve thermal ablation of the tumor cells.”

To optimize the treatment protocol, the researchers used machine learning algorithms to determine the laser power, irradiation time, and concentration of phototherapeutic agent that would lead to the best results.

This led them to develop a laser treatment cycle that lasts about three minutes. During this time, the particles heat up to approximately 50 degrees Celsius, which is enough to destroy tumor cells. Also at this temperature, the polymer matrix inside the particles begins to melt, releasing some of the chemotherapy drug contained in the matrix.

“This laser system, optimized for machine learning, truly allows us to deliver low-dose, localized chemotherapy using deep tissue penetration of near-infrared light for on-demand pulsed photothermal therapy. This synergistic effect results in low systemic toxicity compared to conventional chemotherapy regimens,” says Neelkanth Bardhan, a cancer research fellow in the Belcher lab and second author of the paper.

Elimination of tumors

The researchers tested the microparticle treatment on mice that were injected with an aggressive type of cancer cell from triple-negative breast tumors. Once the tumors were formed, the researchers implanted about 25 microparticles into each tumor and then performed laser treatment three times, with a three-day break between each treatment.

“This is a powerful demonstration of the utility of near-infrared-sensitive material systems,” says Belcher, who with Bardhan previously worked on near-infrared imaging systems for the diagnosis and treatment of ovarian cancer. “Controlling drug release at specific intervals using light after just one dose of particle injection is a game-changer for less painful treatment options and may lead to better patient compliance.”

In mice that received this treatment, the tumors were completely destroyed, and the mice lived much longer than those that were given chemotherapy or phototherapy alone, or no treatment at all. Mice that received all three rounds of treatment also performed much better than those that received only one laser treatment.

The polymer used to make the particles is biocompatible and has already been approved by the FDA for use in medical devices. The researchers now hope to test the particles in larger animal models, with the goal of eventually evaluating them in clinical trials. They expect that this treatment may be useful for any type of solid tumor, including metastatic tumors.