Nanoparticle based targeted codelivery of siRNA and taxane to treat drug resistant HER breast cancer

This SBIR Fast Track application focuses on the development of a nanoconstruct for co delivery of siRNA and chemotherapy drugs to drug resistant human epidermal growth factor receptor type positive HER breast cancer HER breast cancer is a subtype that presents HER overexpression and accounts for of invasive breast cancers HER breast cancer has poor prognosis despite the rigorous current first line treatment using two HER targeted therapies trastuzumab and pertuzumab and one taxane paclitaxel or docetaxel The drug combination requires hours of infusion time costs over $ per treatment course and has many severe adverse events while achieving a progression free survival of only months To address these shortcomings we seek to develop a single therapy that can replace the three drug combination We will incorporate a taxane onto our recently developed nanoconstruct for targeted delivery of siRNA against HER siHER The nanoconstruct is a hybrid of a nm mesoporous silica nanoparticle MSNP and a co polymer coating It is conjugated with HER antibodies for targeted delivery SiRNA is loaded last and was fully protected under PEG layer from blood enzymatic degradation for hours vs andlt min as free siRNA The siHER nanoconstruct reduced andgt HER protein levels and was shown to overcome cancer resistance to trastuzumab and pertuzumab which only block HER activity It induced apoptotic death of HER cells but was safe to HER or organ cells in culture The nanoconstruct had an excellent safety profile in blood immune cells general health kidney and liver of mice Sol gel MSNP synthesis and layer by layer surface modification afford high synthesis reproducibility and scalability MSNP is also known for its high surface area and silanol chemistry suitable for loading hydrophobic drugs like taxanes In mice the siHER nanoconstruct inhibited growth of orthotopic tumors resistant to trastuzumab and paclitaxel but did not eradicate the tumors Thus as in the first line therapy we incorporated a low dose of taxane onto MSNP core of the siHER nanoconstructs which maximized cancer cell death in vitro In Phase I Aim we will further optimize our nanoconstruct in terms of taxane and siHER loading and screen them for optimal size drug release profile efficacy in HER cancer cells and safety to normal cells In Phase II the optimized nanoconstruct will be evaluated for in vivo efficacy and PK profile in Aim and the safety to blood immune cells organ function and overall health of mice in Aim Both primary orthotopic tumor and metastasis models will be utilized with the aforementioned first line therapy as the benchmark Results will provide important data towards an investigational new drug IND application to the FDA This project is a collaboration between PDX Pharmaceuticals LLC specialized in material optimization characterization and screening in vitro and the Dept of Biomedical Engineering and Knight Cancer Institute of the OHSU School of Medicine specialized in cancer biology and drug evaluation in tumor models Project Narrative The first line therapy for drug resistant HER positive breast cancer calls for a combination of two HER targeted therapies pertuzumab and trastuzumab and one chemotherapy drug paclitaxel or docetaxel The combination requires hours of infusion costs over $ per course of treatment and has severe adverse effects while the progression free survival is only months We propose to develop a single nanoparticle based therapy capable of co delivering a chemotherapy drug and a small biomolecule siRNA that can knock down the HER gene resulting in greater efficacy safety and affordability than the current three drug regimen