(141e) Rational Design of Silica-Based Nanoparticles for Overcoming Barriers of siRNA Delivery in Relapsed Prostate Cancer Applications

The use of exogenous siRNA technology to modulate aberrant protein expression resulting from genetic mutations is a promising therapeutic approach for treatment of diseases such as prostate cancer (PC). The promise of siRNA-based therapeutics is dependent on the development of platforms that effectively protect siRNA from nuclease degradation and deliver the siRNA to the cytosol of target cells. The establishment of nanoparticle-based siRNA delivery platforms have been investigated to mitigate the cost and safety issues associated with viral delivery platforms. In this work, we present the development and characterization of a lipid coated mesoporous silica nanoparticle (LC-MSN) to address the need for safe and effective siRNA delivery across various biological barriers in the relapsed prostate cancer landscape. The LC-MSN utilizes calcium silicate nanogating over the silica core to efficiently load (80%) and release (>80%) siRNA in relevant media, as analyzed by tracking a fluorescently tagged siRNA cargo. Additionally, the calcium silicate core is encapsulated in a lipid bilayer aimed to improve the LC-MSN biocompatibility and enables the integration of GRP78 minibodies for targeted delivery to PC cells. The cytotoxicity, uptake and intracellular fate of the LC-MSN is investigated within our work using the LNCaP PC cell line. Furthermore, our work utilizes an ex ovo chick chorioallantoic membrane model (CAM) to assess LC-MSN system vascular margination, binding, circulation time and stability. The structural and chemical versatility of the silica nanoparticle core along with a biocompatible lipid coating makes the LC-MSN a promising candidate for siRNA delivery within the relapsed PC landscape.