Researchers have developed tiny particles designed for implantation at cancer tumor sites to deliver two kinds of treatments: heat and chemotherapy.
Patients facing advanced cancer often undergo several rounds of various treatments, which can lead to unpleasant side effects and may not always be effective.
To broaden treatment possibilities for these patients, scientists at MIT have engineered miniature particles that can be placed directly at the tumor site, providing both heat therapy and chemotherapy.
This method could minimize the side effects typically associated with intravenous chemotherapy, and the combined effect of these two therapies might enhance patient longevity compared to receiving single treatments separately. In studies conducted on mice, the researchers found that this method resulted in the complete disappearance of tumors in most subjects and significantly extended their survival time.
“An area where this technology could be valuable is in managing the growth of rapidly expanding tumors,” states Ana Jaklenec, a principal investigator at MIT’s Koch Institute for Integrative Cancer Research. “Our aim is to help patients who have limited options, potentially extending their lives or at least improving their quality of life during treatment.”
Jaklenec co-authors this study alongside Angela Belcher, the James Mason Crafts Professor of Biological Engineering and Materials Science and Engineering and a member of the Koch Institute, and Robert Langer, an MIT Institute Professor and also affiliated with the Koch Institute. Maria Kanelli, a former MIT postdoctoral researcher, is the lead author of the study, which is published in the journal ACS Nano.
Dual Therapy
Patients with advanced tumors typically receive a mix of treatments such as chemotherapy, surgical procedures, and radiation therapy. An emerging approach known as phototherapy involves the implantation or injection of particles that are heated using an external laser, raising the temperature enough to destroy nearby tumor cells while leaving surrounding tissue unharmed.
Current clinical trial methods for phototherapy utilize gold nanoparticles that generate heat when exposed to near-infrared light.
The MIT research team sought to find a way to simultaneously deliver phototherapy and chemotherapy, believing this combination could ease the treatment experience for patients and possibly yield complementary benefits. They opted for an inorganic compound called molybdenum sulfide as the phototherapeutic agent, known for its efficient conversion of laser light to heat, allowing for the use of lower-powered lasers.
To create a microparticle that could deliver both therapies, the researchers blended molybdenum disulfide nanosheets with one of two types of chemotherapy: doxorubicin, which is water-soluble, or violacein, which is water-insoluble. The production of these particles involved mixing molybdenum disulfide and the drug with a polymer known as polycaprolactone, which was then dried into a film and shaped into microparticles of various forms and sizes.
For this research, they created cubic particles measuring 200 micrometers across. Once injected into the tumor, the particles remain in place throughout the treatment. An external near-infrared laser heats the particles during each treatment cycle. This laser can penetrate tissue depths of several millimeters to centimeters, providing a localized effect.
“This platform offers the benefit of on-demand activation in a pulsatile manner,” says Kanelli. “You can administer it with a single intratumoral injection, and then use an external laser source to activate the system, releasing the medication while simultaneously causing thermal ablation of the tumor cells.”
To refine the treatment protocol, the team employed machine-learning algorithms to determine the optimal laser strength, duration of irradiation, and concentration of the phototherapeutic agent for the best results.
This process led to the formulation of a laser treatment cycle lasting around three minutes. During this period, the particles reach temperatures of approximately 50 degrees Celsius, hot enough to eliminate tumor cells. At this temperature, the polymer matrix within the particles starts to dissolve, releasing the chemotherapy drug encapsulated within.
“This machine-learning-optimized laser technique enables us to provide localized, low-dose chemotherapy while effectively utilizing the deep tissue penetration capabilities of near-infrared light for on-demand photothermal therapy. This synergistic interaction leads to reduced systemic toxicity when compared to traditional chemotherapy treatments,” shares Neelkanth Bardhan, a research scientist at Break Through Cancer in the Belcher Lab and co-author of the study.
Eradicating Tumors
The research team evaluated the microparticle treatment on mice injected with aggressive cancer cells from triple-negative breast tumors. After tumor development, around 25 microparticles were implanted per tumor, and the laser treatment was administered three times, with three-day intervals between each session.
“This serves as a powerful validation of the utility of near-infrared-responsive material systems,” remarks Belcher, who, along with Bardhan, previously worked on near-infrared imaging systems for both diagnosis and treatment in ovarian cancer. “The ability to control drug release at timed intervals using light, following a single administration of particles, represents a significant breakthrough for less painful treatments and can enhance patient adherence to therapy.”
Mice treated in this way had their tumors completely eradicated and lived significantly longer compared to those receiving only chemotherapy, phototherapy alone, or no treatment at all. Furthermore, mice undergoing all three treatment cycles fared considerably better than those treated with just a single laser application.
The polymer used for creating the particles is biocompatible and has already received FDA approval for use in medical devices. The researchers now plan to test the particles in larger animal models, with aspirations of eventually assessing them in clinical trials. They believe this treatment may prove effective for any kind of solid tumor, including metastatic cancers.
