The long-term goal is to develop a multifunctional delivery system for integrated cancer therapy and imaging. The core-shell architecture of nano-vesicles made with novel ABA triblock copolymers poly(2-methyloxazoline)-b-poly(dimethylsiloxane)-b-poly(2-melhyloxazoline) allows for incorporation of hydrophilic molecules (e.g., VEGF silencing siRNA) into the core and hydrophobic drugs (e.g. , paclitaxel) in the shell. Previous studies also show that the nano-vesicles can efficiently deliver siRNA in vitro or deliver Taxol in vivo. In the proposed Phase I studies, the specific aims are: (1) to synthesize and characterize a series of triblock copolymers that assemble into nano-sized vesicles in aqueous medium and encapsulate VEGF gene silencing siRNA and paclitaxel in the core and shell, respectively. The vesicle surfaces will be functionalized with OTPA anhydride to allow for chelation of Gd3+ ions for MRI contrast enhancement, (2) the formulations will be evaluated in-vitro for gene silencing efficacy in endothelial cells (HUVEC) and cytotoxicity in MDA-MB-435 human breast cancer cells, and (3) following optimization of gene silencing and cytotoxicity in vitro, the in vivo imaging and efficacy studies will be performed in an orthotopic estrogen-negative MDA-M8-435 breast cancer xenograft established in female athymic (nu/nu) mice.
