Researchers at Massachusetts General Hospital and Harvard Medical School in Boston have created drug-loaded nanoparticles made from sugar molecules that reprogrammed tumor associated macrophages into an anti-cancer phenotype that, combined with immune checkpoint blockade, caused tumor regression and increased survival in various mouse cancer models.
The nanoparticles were made from cyclodextrin (a sugar molecule) cross-linked with L-lysine (an amino acid). These particles were optimized to both load drugs and deliver them to tumor associated macrophages effectively. For the cargo, the researchers screened a panel of 38 drugs that have been known to reprogram macrophages and settled on a TLR7/8 agonist, which macrophages see as a “danger signal”.
The idea is that the macrophage would see this drug and become activated to help destroy aberrant cells in its vicinity. The researchers discovered that the macrophages internalized these nanoparticles to become a more “antitumor” phenotype, and worked with T-cells to destroy the implanted tumors in mice. While they have strong anti-tumor effects, it’s unclear how the nanoparticles affect the rest of the macrophages in the body, especially those of the liver.
This report is in line with a number of recent papers from the Weissleder Lab and labs around the world to reprogram the immune system to fight cancer. Cancer immunotherapy was ranked the biggest breakthrough in 2012 by the magazine Science, and teams around the world are working on unlocking its potential to cure more patients of cancer. Tumor associated macrophages have been implicated in preventing T cells from doing their cancer-killing jobs, so these macrophage-targeting nanoparticles are poised solve the next hurdle in the immunotherapy story.
The cyclodextrin nanoparticles are formed by FDA-approved individual components, including L-lysine and cyclodextrin, potentiating faster translation to the clinic.
The full results are published in Nature Biomedical Engineering: TLR7/8-agonist-loaded nanoparticles promote the polarization of tumour-associated macrophages to enhance cancer immunotherapy…
Image via Nature Biomedical Engineering…