Nano-siRNA Particles and Combination Therapies for Ovarian Tumor Targeting
Abstract
We propose new modular polymer systems that can generate targeted siRNA in a new stable and highly potent form using safe polymeric systems in place of viruses, which are known to yield undesirable side-effects. Key to these nanomaterial systems is the ability to program-in to a single delivery system specific combinations of chemotherapy drugs with siRNA and molecular inhibitors shown to be effective in ovarian cancer, thus providing the opportunity for highly synergistic couplings of therapeutics delivered in a safe and effective manner. This goal will be accomplished using the biologically intuitive design of nanoparticles using three key innovations, which are examined in Specific Aims 1 through 3: concatenated siRNA systems (csiRNA), layer-by-layer nanoparticle delivery of combination therapies, and polypeptide based linear-dendritic copolymers for siRNA encapsulation. New developments with csiRNA and continued work with the related RNAi microsponges is promising, and greater understanding of these systems will enable the investigation of targets identified by Michael Birrer, including FGF18, that will synergize with the innate immune response of the tumor cells to achieve a highly effective treatment. We continue to develop LbL nanoparticle systems designed specifically to deliver a chemotherapy drug for DNA damage from its interior, and siRNA that can block genes that promote or enable cell survival in the presence of the drug from its exterior. New work in this area includes the successful knockdown of EZH2 and other select targets as a result of collaborations with the Drapkin lab. In vitro work suggests potential for efficacy in these systems, and we will examine the efficacy in vivo in the upcoming year, in particular when using LbL stealth targeting outer layers also developed during this grant period.
Document Details
- Document Type
- Technical Report
- Publication Date
- Aug 01, 2015
- Accession Number
- ADA624483
Entities
People
- Paula T. Hammond
Organizations
- Massachusetts Institute of Technology