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New Nanoparticles Effectively Shrink Ovarian Tumors in Mice

Lauren Ware

A study from Harvard and MIT scientists has uncovered a way to shrink ovarian tumors in mice, leading the way for new therapeutics to treat cancer in humans.

Scientists have a dual mission when it comes to developing new therapeutics to treat cancer: first the drug must target the tumor cells specifically, then it must penetrate the cells effectively to deliver the drug where it can work. A collaboration between Harvard and Massachusetts Institute of Technology (MIT) scientists has achieved both aims, using a new nanoparticle to penetrate and shrink ovarian tumors in mice.

The nanoparticle technology harnessed a naturally occurring phenomenon called RNA interference (RNAi), which delivers short strands of RNA that bind to portions of messenger RNA (mRNA) in the tumor cells, preventing that mRNA from generating its intended protein product. In this case, that protein is a transcriptional factor called ID4, known to be overproduced in some ovarian cancers. The team from Harvard and MIT published its findings online Aug. 15 in Science Translational Medicine.

This schematic shows the tumor-penetrating nanocomplex (TPN) as it makes it way from the bloodstream to the tumor site, where it docks with p32 on the surface of the tumor cell, then enters the endosome and finally, the cytosol, where it silences the mRNA that codes for ID4.

“ID4 operates deep inside the nucleus of the cell,” said William Hahn, an associate professor of medicine at Harvard Medical School and one of the study’s senior authors. “Traditionally, that’s been a hard place to get drugs to.” That’s because even if a drug succeeds in penetrating the outer cell membrane, it often gets “stuck” in the endosome, a membranous pocket within the cell, and can’t reach its intended target further into the cytosol.

In the study, Hahn, along with fellow senior author Sangeeta Bhatia, a biomedical engineer at MIT, and collaborators, created a new type of nanoparticle that effectively targeted and penetrated cancerous tumors to deliver RNA into the cell. The nanoparticles were fitted with a short protein fragment that attached to a protein on tumor cells called p32, discovered by Erkki Ruoslahti, a molecular biologist at the Sanford-Burnham Medical Research Institute at University of California, Santa Barbara, and also one of the paper’s authors.

Once there, the nanoparticle shuts off the gene that codes for ID4, effectively “silencing” the gene’s RNA and preventing ID4 from being produced. Why ID4? It was identified as a possible effective ovarian cancer target by the analysis of cancer genomes. Researchers sequence the genomes of tumor cells for major cancers, generating long lists of proteins that are mutated, amplified, or deleted in certain cancers. “Sequencing gives you an essential blueprint for figuring out what drives cancer growth, although it doesn’t tell you everything,” said Hahn. Using this nanoparticle approach, he said, may give researchers a systematic, time-efficient way to whittle that list down to genes that are important as targets (because they shrink tumors or otherwise disrupt the cancer’s growth) and discard red herrings. ID4, their first test case, was a big win: silencing its gene with the RNAi nanoparticle suppressed tumor growth in mice by 82%.

The study is the first published by a collaboration between Hahn, Bhatia, and colleagues. Hahn is the leader of Project Achilles, an effort to identify new targets for cancer drugs from ongoing genome sequencing efforts. Meanwhile, Bhatia had been using nanotechnology to develop ways to deliver therapeutics to tumors and other tissues. “Colleagues that know both of us said, ‘You two should really meet,’” said Hahn.

The next step for the team is to use the nanoparticle complex to investigate other potential genomic targets for cancer drugs, said Hahn. They are also planning to test the nanoparticle delivery system to see if it can be safely used in humans to deliver RNAi therapeutics.

Keywords:  genomics