Surface-modified nanoparticles enhance transurothelial penetration and delivery of survivin siRNA in treating bladder cancer

Darryl T. Martin, Jill M. Steinbach, Jingchun Liu, Shogo Shimizu, Hristos Z. Kaimakliotis, Marcia A. Wheeler, Adam B. Hittelman, W. Mark Saltzman, Robert M. Weiss

Research output: Contribution to journalArticle

36 Scopus citations

Abstract

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 lowmolecular 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.

Original languageEnglish (US)
Pages (from-to)71-81
Number of pages11
JournalMolecular cancer therapeutics
Volume13
Issue number1
DOIs
StatePublished - Jan 1 2013
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Martin, D. T., Steinbach, J. M., Liu, J., Shimizu, S., Kaimakliotis, H. Z., Wheeler, M. A., Hittelman, A. B., Mark Saltzman, W., & Weiss, R. M. (2013). Surface-modified nanoparticles enhance transurothelial penetration and delivery of survivin siRNA in treating bladder cancer. Molecular cancer therapeutics, 13(1), 71-81. https://doi.org/10.1158/1535-7163.MCT-13-0502