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31st May 2023

MIT researchers develop nanoparticle system for drug delivery

A research team has recently developed a new system that uses nanoparticles to deliver toxic drugs to tumours. Known as bottlebrush particles, these immunostimulatory drugs can allow clinicians to administer medications to tumours in a controlled manner, minimizing the systemic inflammation common with immunotherapy. While in its early stages, the successful results from initial studies show promise for application in clinical practice.

Enhancing tumour targeting and elimination

Bhagchandani’s team, which comprises 18 researchers, shared their work in the April 2023 edition of Science Advances, a journal under the aegis of major scientific publisher Science. The paper is titled ‘Engineering kinetics of TLR7/8 agonist release from bottlebrush prodrugs enables tumour-focused immune stimulation’ and highlights the results of their preliminary studies using mice as study subjects.

In the study, the team designed a library of R848 bottlebrush prodrugs that differed in their R848 release kinetics. R848, generically known as resiquimod, is an exciting drug in cancer immunotherapy because it activates receptors such as Toll-like receptor 7 (TLR7) and TLR8 on immune cells. They aimed to determine whether prodrugs of IMDs could reduce the side effects of the drugs themselves.

The researchers first developed a novel prodrug platform shaped like a bottlebrush. Each bottlebrush is cylindrical, with multiple chains extending from a central backbone, giving it a bottlebrush-like structure. The prodrugs were then bound along the central backbone through cleavable linkers, which defined the rate of release of IMD. They created six bottlebrush prodrugs, allowing them to determine the prodrug release profiles that would be effective in cancer therapy without systemic toxicity.

In preliminary studies in immune cells and mice, the team found that the fastest-releasing prodrugs caused side effects, such as weight loss, reduced white blood cell count, and elevated cytokine levels. The medium and slow-releasing prodrugs did not cause these side effects.

The researchers also tested the prodrugs in two different models of colon cancer in mice. Both models showed significantly slowed tumour growth. When combined with a checkpoint blockade inhibitor, tumours were eliminated in 20% of mice. Their findings also suggest that bottlebrush prodrugs can enhance the immune system’s response to cancer vaccines. “The ability of the bottlebrush prodrug strategy to change both where the drug accumulates in the body and when it is active is very attractive for activating immune responses against cancer or other disease safely,” said Darrell Irvine, a senior author on the paper.

The IMD bottlebrush prodrug project was led by Sachin Bhagchandani, a graduate student in Chemical Engineering at MIT, currently specializing in polymers and soft matter. The paper’s senior authors are Jeremiah Johnson, a professor of Chemistry at MIT, and Darrell Irvine, the Underwood-Prescott Professor at MIT’s departments of Biological Engineering and Materials Science and Engineering. Farrukh Vohidov, Lauren Milling, Evelyn Yuzhou Tong, Christopher Brown, and Michelle Ramseier were also on the project. Other team members are Bin Liu, Timothy Fessenden, Hung Nguyen, Gavin Kiel, Lori Won, Robert Langer, Stefani Spranger, and Alex Shalek.

The research was funded by the Marble Center for Cancer Nanomedicine, MIT; the Ragon Institute of Mass General, MIT; and Harvard, in addition to the Koch Institute Frontier Research Program. Additional funding came from a graduate fellowship from the Ludwig Center at the Koch Institute and the National Cancer Institute.

Nanoparticles for cancer immunotherapy

Nanoparticle system developed by MIT researchers.
Nanoparticles are minute particles, typically 1 to 100 nanometers in size, with distinct physical and chemical properties from larger materials, and they are invisible to the naked eye.

Typically, immunostimulatory prodrugs work by provoking the immune system to attack cells within the vicinity of a tumour by activating the immune system in some way. These immunostimulatory drugs are administered intravenously – by injection into the veins – where they typically produce significant systemic inflammation. To improve the precision of this form of therapy while maximizing the immunostimulatory capacity of these drugs, researchers at MIT have designed a new type of prodrug with bottlebrush-like structures.

Immunotherapy has been long explored as a viable solution to cancer therapy, but it has not been without its disadvantages. Theoretically, the system works this way: a clinician administers a small molecule drug, activating immune cells. Immune cells such as B cells produce cytokines, which will cause the migration of basophils and other inflammatory cells, leading to a local inflammatory response within the tumour. In actuality, this solution comes with a risk of causing inflammation in non-cancerous tissue. Systemic inflammation is a common side effect of immunotherapeutic cancer solutions. Researchers and clinicians have looked for ways to minimise the side effects of this form of cancer therapy.

Sachin Bhagchandani, one of the researchers on the project, spoke on the goal of the team to decouple systemic toxicity from immunotherapeutic solutions. By altering the structure of these nanoparticles, they were able to change their release profile. This allows them to accumulate at the tumour and cause immunostimulation primarily at those sites without causing inflammation elsewhere. This new nanoparticle structure, called the bottlebrush nanoparticle, features a central backbone and ‘bristles” emanating from the backbone. Immunostimulatory drugs in an inactive form (known as prodrugs) can be conjugated to the main backbone, with cleavable chemical linkers that allow the release of drugs to be finetuned.

In their latest work, the researchers tested six nanoparticle formations designed to release a particular class of immunostimulatory drugs – known as imidazoquinolines (IMDs) – at different rates. Imidazoquinolines are a class of immune response modifiers that activate monocytes, macrophages, and natural killer cells to produce cytokines. These drugs can also activate antigen-presenting dendritic cells, which can stimulate cytotoxic T-lymphocytes, a class of cells responsible for clearing foreign or damaged cells from circulation.

In the mouse tumour model the researchers tested, they found that the medium and slow-release versions produced no side effects. In addition, these versions were more effective at reducing cancerous growth. On the other hand, the fast-releasing nanoparticles delivered significant damage to non-cancerous tissue, with a greater degree of systemic inflammation. As Bhagchandani, currently a PhD student in Chemical Engineering at MIT and lead author of the study, surmised, “If you minimise release of the active compound there [in the blood], then you’re able to get anti-tumour effects at the tumour site without the systemic side effects.” By controlling the release rates of the drugs, they were able to minimise the effects on systemic tissues, showing great promise for human cancer therapy in the future.

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