Researchers have shown for the first time that a targeted nanoparticle can move into tumors, deliver pieces of genetic material and turn off an important cancer gene using RNA interference, or RNAi.
The team, led by California Institute of Technology scientists, included City of Hope’s Yun Yen, M.D., Ph.D., Dr. & Mrs. Allen Y. Chao Chair in Developmental Cancer Therapeutics. The scientists published the work in the March 21 advance online edition of Nature.
 Yun Yen (Photo by Kaminsky Productions) |
Researchers injected nanoparticles — tiny engineered molecules — into the bloodstream of cancer patients in a clinical trial. They found the nanoparticles could deliver double-stranded small interfering RNAs (siRNAs) to a gene that expresses the enzyme known as ribonucleotide reductase.
It also was the first demonstration that this new type of therapy is dose-dependent: Higher numbers of nanoparticles sent into the body led to higher numbers of nanoparticles in the tumor cells.
The results demonstrate the feasibility of using both nanoparticles and RNAi-based therapeutics in patients and open the door for future therapeutics that attack cancer and other diseases at the genetic level, says Mark Davis, Ph.D., the Warren and Katharine Schlinger Professor of Chemical Engineering at Caltech and the research team’s leader.
RNA interference is the mechanism by which double strands of RNA silence genes. Experts believe this type of gene inhibition has the potential to lead to treatments for diseases such as cancer, and Beckman Research Institute of City of Hope scientists are among the leaders in this developing field.
Still, scientists have found roadblocks to the application of RNAi technology as therapy. One of the most problematic is finding a way to move the therapeutic agents, which are made up of fragile siRNAs, into tumor cells. Davis and his team, however, created a system containing four components — including a unique polymer — that can self-assemble into a targeted, siRNA-containing nanoparticle.
The siRNA delivery system is under clinical development by Calando Pharmaceuticals Inc., a Pasadena-based nanobiotech company.
“These nanoparticles are able to take the siRNAs to the targeted site within the body,” said Davis. Once they reach their target — in this case, the cancer cells within tumors — the nanoparticles enter the cells and release the siRNAs.
The results in Nature are from a phase I clinical trial among cancer patients that began in 2008.
“Promising data from the clinical trials validates our years of research at City of Hope into ribonucleotide reductase as a target for novel gene-based therapies for cancer,” said Yen, associate director for translational research in the comprehensive cancer center and co-leader of the Developmental Cancer Therapeutics Program. “We are seeing for the first time the utility of siRNA as a cancer therapy and how nanotechnology can target cancer cells specifically.”
In addition to Davis and Yen, coauthors include Antoni Ribas, M.D., and David Seligson, M.D., of the University of California, Los Angeles (UCLA), Anthony Tolcher, M.D., of South Texas Accelerated Research Therapeutics, Chung Hang Choi, a Caltech student, Christopher Alabi, Ph.D., at the Massachusetts Institute of Technology, and Jeremy Heidel of Calando Pharmaceuticals. Co-author Jonathan Zuckerman is a student at both UCLA and Caltech.
The National Cancer Institute and the Daljit S. and Elaine Sarkaria Biomarker Laboratories supported part of the research.
Shawn Le and Alicia Di Rado contributed to this story.
