The 2006 Nobel Prize in Physiology or Medicine was awarded jointly to Andrew Z. Fire and Craig C. Mello for their 1998 discovery of RNA interference (RNAi), gene silencing by double-stranded RNA.
Today, RNAi-based therapeutics are in Phase II and Phase III clinical trials. The rapid development of this technology demonstrates its enormous potential for treatment of a range of diseases.
A major hurdle for clinical applications is the safe and effective delivery of small interfering RNA (siRNA). Unlike biologics that target membrane proteins, siRNA molecules need to enter the cytosol of diseased cells to work. In addition, unlike small molecules that diffuse freely across the cell membrane, siRNA molecules are large and negatively charged. They cannot easily and independently cross the cell membrane.
Current siRNA nanoparticle delivery platforms in clinical trials, such as cationic lipoplexes and polyplexes, induce transient gene silencing; they lack a sustained siRNA release property. In vitro studies have indicated that efficacy, in general, lasts less than two weeks at the cellular level.
A new lipid-polymer hybrid nanoparticle combines a cationic liposome system with a controlled-release polymer technology, allowing siRNA encapsulation along with sustained release. Encapsulation of the siRNA would be very low if it depended solely on the noncharged, controlled-release polymer technology. Sustained delivery allows for longer activity, and, potentially, subsequent lower dosage and injection frequencies.
An in vitro proof-of-concept study showed that the lipid-polymer hybrid nanoparticle slowly releases the siRNA over the course of a month, allowing sustained knockdown of PHB1, a protein involved in cell proliferation, apoptosis, chemoresistance, and other biological processes in lung carcinoma cells.
“It takes a long time to discover a drug or small molecule to target a protein of interest, plus there are many undruggable proteins. The beautiful thing about RNAi technology is you can target any protein you want by silencing the gene,” explains Jinjun Shi, Ph.D., assistant professor, Laboratory for Nanoengineering and Drug Delivery, Department of Anesthesiology, Brigham and Women’s Hospital, Harvard Medical School.
The new lipid-polymer hybrid nanoparticle technology is initially intended for use in fundamental research and target validation. The goal is to eventually extend its application to the clinic as a vehicle for delivering therapeutic siRNAs and, perhaps, for co-delivering chemotherapeutics and siRNAs for synergistic cancer treatment.