“This is a proof of concept, but we’ve demonstrated there is now a new tool for introducing anti-cancer drugs directly into cancer cells – and that should make drug treatments significantly more effective,” says Dr. Zhen Gu, senior author of a paper on the research and an assistant professor in the joint biomedical engineering program at NC State and UNC-Chapel Hill.
The nanoparticles are packed with DNA molecules that are embedded with an anti-cancer drug called doxorubicin. Image: Ran Mo. (Click to enlarge.)
Gu’s research team developed spherical nanoparticles coated with a shell that incorporates hyaluronic acid (HA), which interacts with proteins found on the surface of some cancer cells. When a targeted cancer cell comes into contact with the HA, the cell absorbs the entire nanoparticle.
Once inside the cancer cell, the nanoparticle’s shell comes apart, releasing its payload: a collection of complex DNA molecules that are embedded with an anti-cancer drug called doxorubicin (Dox), which targets the nucleus of the cancer cell.
The DNA molecules are designed to unfold – and release the Dox – only when they come into contact with high ATP levels. High levels of ATP are normally only found inside a cell, which means the Dox is released within striking distance of the nucleus – and not inadvertently released outside the cell.
“This is the first time ATP has been used as a molecular trigger for controlled release of anti-cancer drugs, both in vitro and in vivo,” says Dr. Ran Mo, lead author of the paper and a postdoctoral researcher in the joint biomedical engineering program. ATP transports chemical energy within cells for metabolism.
In in vitro testing, the new technique was 3.6 times more effective against MDA-MB-231 human breast cancer cells than techniques that don’t incorporate an ATP-targeting component.
The researchers also tested the new technique in an in vivo model, using mice that had breast cancer tumors. The researchers found that the ATP-targeting technique was significantly more effective at inhibiting tumor growth compared with other techniques.
“We also believe that we’ll be able to make the technique even more targeted by manipulating ATP levels in specific areas,” Gu says.
The paper, “ATP-triggered anticancer drug delivery,” was published March 11 in Nature Communications. Co-authors from Gu’s lab include Tianyue Jiang, a Ph.D. student; Rocco DiSanto, a master’s student; and Dr. Wanyi Tai, a postdoctoral researcher. The research was supported by the National Institutes of Health under grant 1UL1TR001111 and funding from NC State.
Note to Editors: The study abstract follows.
“ATP-triggered anticancer drug delivery”
Authors: Ran Mo, Tianyue Jiang, Rocco DiSanto, Wanyi Tai, and Zhen Gu, North Carolina State University and University of North Carolina at Chapel Hill
Published: March 11, 2014, Nature Communications
Abstract: Stimuli-triggered drug delivery systems have been increasingly used to promote physiological specificity and on-demand therapeutic efficacy of anticancer drugs. Here we utilize adenosine-5’-triphosphate (ATP) as a trigger for the controlled release of anticancer drugs. We demonstrate that polymeric nanocarriers functionalized with an ATP-binding aptamer-incorporated DNA motif can selectively release the intercalating doxorubicin via a conformational switch when in an ATP-rich environment. The half-maximal inhibitory concentration (IC50) of ATP-responsive nanovehicles is 0.24 [micrometer] on MDA-MB-231 cells, a 3.6-fold increase in the cytotoxicity compared with that of non-ATP-responsive ones. Equipped with an outer shell crosslinked by hyaluronic acid, a specific tumour-targeting ligand, the ATP-responsive nanocarriers present an improvement in the chemotherapeutic inhibition of tumour growth using xenograft MDA-MB-231 tumour-bearing mice. This ATP-triggered drug release system provides a more sophisticated drug delivery system, which can differentiate ATP levels to facilitate the selective release of drugs.