Efforts to treat cancer using genes and other oligonucleotides, such as short interfering RNA (siRNA), that turn off the biochemical processes that trigger malignancies have been hindered by difficulties in delivering nucleic acids to tumors.
Nanoparticles hold promise for solving these issues, and a recent report from researchers at the Singapore Agency for Science, Technology and Research demonstrates that nanoparticle-based oligonucleotide delivery systems can also deliver drugs to tumors, increasing the therapeutic effect of both agents.
Reporting its work in the journal Nature Materials, a research team headed by Yi-Yan Yang, Ph.D., describes its development of a novel core-shell nanoparticle made of a biodegradable polymer. This polymer contains both water-soluble, or hydrophilic, and fat-soluble, or hydrophobic, components, which causes the polymer to self-assemble into a core-shell structure when dissolved in water. The core consists of a hydrophobic, cholesterol-rich region, providing a suitable environment for entrapping large quantities of water-insoluble drugs such as paclitaxel. At the same time, the hydrophilic nanoparticle shell creates a stable environment for binding nucleic acid therapeutics, including DNA and siRNA.
To determine if these nanoparticles could successfully deliver their payload to tumor cells, the investigators used a construct containing a gene that expresses green fluorescent protein as well as paclitaxel and added this nanoparticle to breast cancer cells growing in culture. This experiment showed that gene expression did occur within the cells, and that the addition of paclitaxel had no significant effect on GFP production.
With this positive result in hand, the investigators then prepared a nanoparticle containing paclitaxel and a gene coding for a protein known as interkeukin-12. The researchers also prepared nanoparticles containing either paclitaxel or the siRNA agent, but not both. They then administered these nanoparticles to mice with human breast tumors and found that the combination nanoparticle was far more effective at suppressing tumor growth than were either of the single agent nanoparticles. The investigators obtained similarly positive results using a nanoparticle containing paclitaxel and an siRNA designed to suppress production of the protein Bcl-2, which is known to play a role in tumor growth by inhibiting apoptosis, or programmed cell death.
This work is detailed in a paper titled, “Co-delivery of drugs and DNA from cationic core-shell nanoparticles self-assembled from a biodegradable copolymer.” Investigators from the Nanyang Technological University in Singapore also participated in this study. An abstract of this paper is available through PubMed. View abstract.