Nanoparticle delivers antisense agent to tumors

A multifunctional drug delivery system consisting of a lipid-based nanoparticle, a standard anticancer drug, and a short nucleic acid designed to augment the activity of that drug has demonstrated the ability to treat drug-resistant tumor cells.

This work, published in the journal Clinical Cancer Research, suggests a novel approach to treating drug-resistant tumors, the leading cause of cancer deaths.

Tamara Minko, Ph.D., of Rutgers University, led the team of investigators that developed this novel nanotherapeutic system for treating cancer. She and her colleagues set out to target a signaling pathway that causes tumors to trigger new blood vessel growth and to develop resistance to many anticancer drugs. To shut down this pathway, the investigators developed an antisense oligonucleotide that would bind to and inactivate messenger RNA coding for a protein known as hypoxia-inducible factor-1á, which, when present, activates the targeted pathway.

To deliver this antisense agent to tumor cells, the investigators created a lipid-based nanoparticle, or liposome, that would stably incorporate both the antisense agent and the anticancer drug doxorubicin. The investigators also created two additional liposomes as controls, each of which was loaded with only one of the two therapeutic agents. Tests with both isolated tumor cells and with animals bearing human tumors showed that administration of the multifunctional nanoparticle was more effective at killing tumor cells than was coadministration of the two single-component liposomes. At the same time, the multifunctional liposome produced fewer side effects than did the combination of the two single-component liposomes. The investigators hypothesized that cells may have a limited ability to take up liposomes, so including both drugs in a single liposome would increase cellular uptake of the active ingredients relative to when these agents are delivered using two separate liposomes.

This work, which was supported by the NCI, is detailed in the paper "Nonviral Nanoscale-Based Delivery of Antisense Oligonucleotides Targeted to Hypoxia-Inducible Factor 1á Enhances the Efficacy of Chemotherapy in Drug-Resistant Tumor." Investigators from George Mason University, Georgetown University Medical Center, and the Cancer Institute of New Jersey also participated in this study. An abstract of this paper is available at the journal's Web site. View abstract