Development of Chol-DsiRNA Polyplexes to Improve the Therapy of Breast Cancer

DESCRIPTION provided by applicant Breast cancer is the most common type of cancer in women between the ages of and and responsible for deaths annually If treated early five year survival rates for patients in the U S are between and but drop to once metastatic breast cancer has developed Thus there is a great need to develop more effective treatment strategies for metastatic breast cancer RNA interference RNAi can selectively and persistently decrease the expression of any protein at the mRNA level through the cytosolic localization of sequence specific RNAi molecules including small interfering RNA siRNA dicer substrate siRNA DsiRNA and microRNA miRNA Thus RNAi molecules have tremendous potential to improve the treatment of cancer where the suppression of a single or multiple proteins can produce a therapeutic effect and or increase the efficacy of current cancer treatments Our long term goal is to improve the treatment of metastatic breast cancer with RNAi The potencies of RNAi molecules after i v administration however are insufficient for clinical application Modifying the sense strand of siRNA with andapos cholesterol Chol siRNA increases the activity of nuclease resistant siRNA siRNA in the liver and jejunum of mice after i v administration but requires a relatively high dose Our strong preliminary data show that complexation of Chol siRNA or Chol DsiRNA with PLL PEG K a block copolymer of poly L lysines and kDa polyethylene glycol greatly increases potency in primary murine syngeneic breast tumors after i v administration at a much lower dose Chol DsiRNA polyplexes however have higher loading protect Chol DsiRNA from degradation in serum more effectively and suppress mRNA in primary murine syngeneic breast tumors for a longer duration than Chol siRNA polyplexes Thus the overall objectives of this one year proposal are to i provide an initial assessment of the effect of complexation with PLL PEG K on the toxicity PK and distribution of Chol DsiRNA after i v administration and ii obtain proof of concept data that complexation with PLL PEG K is likely to increase the potency of Chol DsiRNA against therapeutically relevant mRNA targets in primary breast tumors and metastases in early and late stage disease We will accomplish our objectives through the following Specific Aims SA Determine the effect of complexation with PLL PEG K on the toxicity pharmacokinetics and distribution of Chol DsiRNA The objective of this aim is to provide an initial assessment of the toxicity PK and distribution of Chol DsiRNA after i v administration of Chol DsiRNA polyplexes in a small animal model SA Determine the activity of Chol DsiRNA polyplexes in primary murine breast tumors and metastases The objective of this aim is to obtain proof of concept data that Chol DsiRNA polyplexes are likely to be active against therapeutically relevant mRNA targets in primary breast tumors and metastases Our approach is innovative because it is a simple and feasible strategy to increase the potency of Chol DsiRNA in target cells relevant to metastatic breast cancer including microvascular endothelial and tumor epithelial cells PUBLIC HEALTH RELEVANCE The proposed research is relevant to public health because the development of Chol DsiRNA polyplexes is expected to improve the therapy of breast cancer and other solid tumors Thus the proposed research is relevant to the part of NIHandapos s mission to foster the application of innovative research strategies to ultimately protect and improve health