Nano-siRNA Particles and Combination Therapies for Ovarian Tumor Targeting
Annual rept. 22 Jul 2013-21 Jul 2014
MASSACHUSETTS INST OF TECH CAMBRIDGE
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New therapies based on RNA interference RNAi show promise for the treatment of ovarian cancer, however, the packaging and delivery of these medicines to tumor sites remains a challenge that has hindered their clinical use. We have been developing new strategies to generate and assemble nanoparticles for RNAi based therapy with enhanced stability to improve tumor delivery. Using a unique method for making RNA called rolling circle transcription, we have generated novel siRNA containing structures. These RNA structures consist of long, repeating siRNA sequences termed concatemeric siRNA csiRNA along with sponge like particles that contain both RNA and inorganic nanocrystals. By combining these materials with different polymers we obtain stable nanoparticles that show prolonged blood circulation, accumulate in tumors, and can silence gene expression in cancer cells. Our current work investigates the use of these nanoparticles to target genes that have been implicated in the progression of ovarian cancer. We have demonstrated the ability to incorporate sequences for more than one siRNA, thus enabling knockdown of multiple genes using the same construct, and we are now investigating efficacy in vitro and in vivo against oncogenic targets in ovarian cancer. New approaches to combination therapy that we are developing use the strategy of staged release of two or more chemotherapeutics from a singular targeted nanoparticle, preceded by the release of siRNA that knocks down genes enabling resistance to the chemotherapy agents. This is accomplished by building a nanoparticle layer by layer, starting with a core that contains a chemotherapy drug relevant to ovarian cancer, such as cisplatin then a second therapeutic is introduced in the outer layers of the particle such as an inhibitor that can lower or impede the function of tumor cells, or siRNA molecules that can turn off a survival gene used by resistant tumor cell types to avoid attack by chemotherapy treatment.
- Medicine and Medical Research