Surface-modified nanoparticles enhance transurothelial penetration and delivery of survivin siRNA in treating bladder cancer.
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 (NP) were modified by addition of a low molecular weight (2.5 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 the capacity to transport large amounts of siRNA across the urothelium and/or to the tumor site, thus increasing therapeutic response.
Corresponding Author: Darryl T. Martin, Department of Urology, Yale University School of Medicine, 789 Howard Avenue, Fitkin 3, P.O. Box 208058, New Haven, CT 06520-8058. darryl.martin@yale.edu.
Darryl T
DT
Martin
Jill M
JM
Steinbach
Jingchun
J
Liu
Shogo
S
Shimizu
Hristos Z
HZ
Kaimakliotis
Marcia A
MA
Wheeler
Adam B
AB
Hittelman
W
W
Mark Saltzman
Robert M
RM
Weiss
D000818:Animals; D048271:Chitosan / Q000737:chemistry; D004337:Drug Carriers; D016503:Drug Delivery Systems; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics*; D051379:Mice; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000235:genetics; D013499:Surface Properties; D000077022:Survivin; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy / Q000235:genetics*; D019459:Urothelium / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
C107489:BIRC5 protein, human; D004337:Drug Carriers; D051034:Inhibitor of Apoptosis Proteins; D034741:RNA, Small Interfering; D000077022:Survivin; D048271:Chitosan