Nanoparticle-based targeted codelivery of siRNA and taxane to treat drug-resistant HER2+ 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 typepositiveHERbreast cancerHERbreast cancer is a subtype that presents HERoverexpression and accounts forof invasive breast cancersHERbreast cancer has poor prognosis despite the rigorous current first line treatment using two HERtargeted therapiestrastuzumab and pertuzumaband one taxanepaclitaxel or docetaxelThe drug combination requireshours of infusion timecosts over $per treatment courseand has many severe adverse eventswhile achieving a progression free survival of onlymonthsTo address these shortcomingswe seek to develop a single therapy that can replace the three drug combinationWe will incorporate a taxane onto our recently developed nanoconstruct for targeted delivery of siRNA against HERsiHERThe nanoconstruct is a hybrid of anm mesoporous silica nanoparticleMSNPand a co polymer coatingIt is conjugated with HERantibodies for targeted deliverySiRNA is loaded last and was fully protected under PEG layer from blood enzymatic degradation forhoursvsandltmin as free siRNAThe siHERnanoconstruct reduced andgtHERprotein levelsand was shown to overcome cancer resistance to trastuzumab and pertuzumabwhich only block HERactivityIt induced apoptotic death of HERcellsbut was safe to HERor organ cells in cultureThe nanoconstruct had an excellent safety profile in bloodimmune cellsgeneral healthkidney and liver of miceSol gel MSNP synthesis and layer by layer surface modification afford high synthesis reproducibility and scalabilityMSNP is also known for its high surface area and silanol chemistrysuitable for loading hydrophobic drugs like taxanesIn micethe siHERnanoconstruct inhibited growth of orthotopic tumors resistant to trastuzumab and paclitaxel but did not eradicate the tumorsThusas in the first line therapywe incorporated a low dose of taxane onto MSNP core of the siHERnanoconstructswhich maximized cancer cell death in vitroIn Phase IAimwe will further optimize our nanoconstruct in terms of taxane and siHERloading and screen them for optimal sizedrug release profileefficacy in HERcancer cellsand safety to normal cellsIn Phase IIthe optimized nanoconstruct will be evaluated for in vivo efficacy and PK profile in Aimand the safety to bloodimmune cellsorgan function and overall health of mice in AimBoth primary orthotopic tumor and metastasis models will be utilizedwith the aforementioned first line therapy as the benchmarkResults will provide important data towards an investigational new drugINDapplication to the FDAThis project is a collaboration between PDX PharmaceuticalsLLCspecialized in material optimizationcharacterizationand screening in vitroand the Deptof Biomedical Engineering and Knight Cancer Institute of the OHSU School of Medicinespecialized in cancer biology and drug evaluation in tumor models Project Narrative The first line therapy for drug resistant HERpositive breast cancer calls for a combination of two HERtargeted therapiespertuzumab and trastuzumaband one chemotherapy drugpaclitaxel or docetaxelThe combination requireshours of infusioncosts over $per course of treatmentand has severe adverse effectswhile the progression free survival is onlymonthsWe propose to develop a single nanoparticle based therapy capable of co delivering a chemotherapy drug and a small biomoleculesiRNAthat can knock down the HERgeneresulting in greater efficacysafety and affordability than the current three drug regimen