26 March 2010
RNA interference (RNAi) is a naturally occurring gene silencing mechanism that prevents expression of transcribed genes via double-stranded RNA molecules. The discovery of this mechanism won a Nobel prize in 2006 (see previous news) and the therapeutic potential of this process to silence the expression of harmful disease-associated genes has been the subject of intense research through the development of small double-stranded RNA molecules called short interfering RNAs (siRNAs). However, in vivo delivery of siRNAs remains a major obstacle to progress with this form of therapy; intravenous injection and viral vector mediated delivery have had very limited success, with generally poor tissue uptake. A recent report in the journal Nature, describes the use of a nanoparticle delivery system to deliver siRNA to tumours in patients with skin cancer (reported by Nature News).
In their paper, Davis et al. describe some initial finding from a phase I clinical trial assessing this technique in fifteen patients [Davis et al. (2010) Nature doi: 10.1038/nature08956]. The delivery system consists of particles approximately 70nm in diameters made up of two synthetic polymers, a protein (human transferrin protein) which engages with receptors on the surface of cancer cells and the siRNA molecule. The particles are delivered into the patients’ bloodstream where they circulate until they come into contact with solid tumours. The transferrin protein then allows targeting of the siRNA into tumour cells that are over expressing the transferrin protein receptor. Once inside the tumour the siRNA is released from the complex and acts to reduce the expression of a particular protein – in this case RRM2.
Tumour samples from three patients were analysed to assess the effectiveness of this therapy. The nanoparticles were found to localise within tumour tissue and not in nearby tissue and their accumulation was dose-dependant. In addition, the researchers measured levels of RRM2 mRNA and protein in the tumour tissue. These were reduced post-treatment in one patient; however, they were unable to determine the magnitude of the reduction. The authors acknowledge that although this study demonstrates it is possible to achieve targeted delivery of siRNAs, many issues will still need to be resolved including, the safety of the treatment and its ultimate impact in influencing tumour growth.
A further use of nanoparticles reported recently is for diagnosis of prostate cancer (see Nature News). This new assay utilises gold nanoparticles linked together by a peptide (short protein) that can be cleaved by an enzymes linked to prostate cancer. Cleavage causes a colour change reaction, even in the presence of very small amounts of enzyme. So far the assay has been shown to be highly sensitive using purified protein, but the sensitivity with actual biological samples has yet to be demonstrated. The ability to detect very small amounts of a biomarker make this assay potentially useful in cancer therapy; early diagnosis of cancer recurrence makes effective treatment more likely, but cancer biomarkers are usually only present in very small amounts at this stage and hard to detect by standard methods.