New drug delivery platform reduces the systemic toxicity associated with conventional chemotherapy.
A new drug delivery method developed by researchers at the Wyss Institute at Harvard University, Boston Children's Hospital and Harvard Medical School uses low-energy ultrasound waves to cause sustained-release nanoparticles loaded with chemotherapeutic agents to deliver their payloads to specific tumor sites. In mouse models of breast cancer, the targeting efficacy was improved two-fold, leading to a measurable reduction in not only the size of the tumor but also drug-related toxicity.
The method involves the use of nanoparticle aggregates (NPAs), or nanoparticles containing the active pharmaceutical ingredient (API) that are surrounded by a matrix. To develop the drug delivery platform, the researchers investigated the impact of nanoparticle size and the nanoparticle-to-matrix ratio on the stability of the NPAs, which need to retain their structure during injection but then disperse when exposed to low-energy ultrasound waves. Once freed from the aggregates, the nanoparticles slowly release the API.
Nanoparticle penetration into the tumor was first confirmed. Both free nanoparticles and NPAs that had been exposed to ultrasound waves provided similar results. Similar tests were then conducted using nanoparticles containing the chemotherapy agent doxorubicin, and it was confirmed that cell death was similar for the free agent and the loaded NPAs. As a last evaluation, the performance of loose, loaded nanoparticles was compared to that of loaded NPAs that were exposed to ultrasound waves. Both were injected intravenously into mice with breast cancer tumors.
The ultrasound-treated NPAs delivered nearly five times the amount of nanoparticles to the tumor site as intact NPAs, while loose nanoparticles delivered two to three times that amount. In addition, when just one-tenth of the dose of doxorubicin usually required was loaded in the NPAs, the tumor size was still reduced by half. As a result, the number of mouse deaths due to drug toxicity was lowered from 40% to 0%. Furthermore, the NPAs limited the "burst release" of the chemotherapy agent, an issue that is commonly observed with injected drugs; the NPAs released just 1.18% of the drug within 5 minutes (compared to 25% for loose nanoparticles).
Further research is needed to improve the performance of the NPAs, and the team is interested in exploring their use in combination with other treatments that target tumors, such as peptides that recognize tumor microenvironments.
"We essentially have an external activation method that can localize drug delivery anywhere you want it, which is much more effective than just injecting a bunch of nanoparticles," says co-first author Netanel Korin, Ph.D., former Wyss Technology Development Fellow and current Assistant Professor at the Israel Institute of Technology.
Adds Anne-Laure Papa, Ph.D., co-first author and Postdoctoral Fellow at the Wyss Institute: "Locking nanoparticles up in NPAs permits precise delivery of an army of nanoparticles from each single NPA directly to the tumor in response to ultrasound, and this greatly minimizes the dilution of these nanoparticles in the bloodstream. Additionally, our ultrasound-triggered NPAs displayed distribution patterns throughout the body similar to the FDA-approved PLGA polymer nanoparticles, so we expect the NPAs to be comparably safe."