Researchers at MIT have developed a nanoparticle system that is designed to deliver immunostimulatory drugs to tumors. These drugs are intended to stimulate immune cells in the vicinity of tumors to begin destroying tumor cells, but when delivered systemically they cause unacceptable dose limiting side-effects such as systemic inflammation. These particles are bottle-brush shaped, with the inactive drug being conjugated to the “brush backbone”. By tweaking the formulation of the particles, the researchers can fine tune their release profile, and have been able to create particles that will accumulate at the tumor without causing side-effects elsewhere.
Training our immune system to destroy tumors is a promising anti-cancer treatment strategy, and has a certain elegance compared with traditional chemotherapeutics. However, this approach is not without its limitations, with possible side-effects such as high levels of systemic inflammation. There are different methods for immunotherapy against tumors, and one involves administering small molecule drugs that can activate immune cells and stimulate them to begin producing cytokines that will cause a local inflammatory response and help to destroy the tumor.
At least that’s the theory. In reality, administering such drugs throughout the body risks high levels of systemic inflammation, promoting these researchers to develop a nanoparticle system to deliver them directly to the tumor. These bottle brush nanoparticles feature a central backbone and ‘bristles’. The immunostimulatory drugs can be conjugated to the central backbone in an inactive form, known as a pro-drug, using chemical linkers that can be cleaved within the body, allowing the researchers to fine-tune the release.
“Our bottlebrush prodrug library enabled us to show an immunological effect of controlling immunotherapy kinetics, allowing us to boost immune responses while minimizing the side effects,” said Sachin Bhagchandani, a researcher involved in the study. “This kind of approach opens up avenues for scientists who want to decouple toxicity from some promising immunotherapy agents.”
To date, the researchers have tested a panel of six nanoparticle formulations that were all designed to release a class of immunostimulatory drug called imidazoquinolines (IMDs) at slightly different rates. In a mouse tumor model, the medium and slow release versions of the particles produced no side-effects, while having significant efficacy in reducing tumor growth, whereas the fast releasing particles caused systemic inflammation.
“Our molecules were able to safely reduce these effects by controlling how much of the active drug is released in the blood,” said Bhagchandani. “If you minimize release of the active compound there, then you’re able to get anti-tumor effects at the tumor site without the systemic side effects.”
Study in journal Science Advances: Engineering kinetics of TLR7/8 agonist release from bottlebrush prodrugs enables tumor-focused immune stimulation