Surface modified nanoparticles enhance transurothelial penetrationand delivery of survivin siRNA in treating bladder cancer

摘要

Penetration of the bladder permeability barrier (BPB) is a major challenge when treating bladder diseases via intravesical delivery. To increase transurothelial migration and tissue and tumor cell uptake, poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) were modified by addition of a low molecular weight (2.5 kDa or 20 kDa) positively charged mucoadhesive polysaccharide, chitosan, to the NP surface. In designing these NPs, we balanced the adhesive properties of chitosan with the release and bioactivity of the siRNA. Chitosan functionalized NPs demonstrated increased binding to and uptake in intravesically instilled mouse bladders and human ureter at 10 times the level of unmodified NPs. Furthermore, we extended the bioactivity of survivin siRNA in vitro for up to 9 days and demonstrated a decrease in proliferation when using chitosan modified NPs relative to unmodified NPs. In addition, treatment of xenograft tumors with chitosan modified NPs that encapsulate survivin siRNA (NP-siSUR-CH2.5) resulted in a 65% reduction in tumor volume and a 75% decrease in survivin expression relative to tumors treated with blank chitosan NPs (NP-Bk-CH2.5). Our low molecular weight chitosan delivery system has thecapacity to transport large amounts of siRNA across the urothelium and/or to thetumor site thus increasing therapeutic response.