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Intravesical instillation of surface-modified nanoparticles to enhance uptake and facilitate site-specific delivery of therapeutic agents for bladder diseases
Hristos Z. Kaimakliotis, MD1, Darryl Martin, PhD1, Christopher J. Hoimes, MD1, Gregory Tew, PhD2, W Mark Saltzman, PhD1, Robert M. Weiss, MD1.
1Yale University School of Medicine, New Haven, CT, USA, 2University of Massachusetts, Amherst, MA, USA.

Intravesical instillation of surface-modified nanoparticles to enhance uptake and facilitate site-specific delivery of therapeutic agents for bladder diseases
ABSTRACT
Introduction and Objective: The potential for intravesical delivery of surface-modified nanoparticles (NPs) to enhance uptake and facilitate site-specific delivery of therapeutic agents for the treatment of overactive bladder and urothelial cancer was investigated using ex vivo, in vitro and in vivo models. A novel, synthetic antimicrobial polymer with cell-penetrating properties, poly-guanidiunium-oxanorborene (PGON), was utilized in the surface-modification of the NPs.
Methods: Fluorophores, coumarin-6 (C6) or Nile Red (NR), were encapsulated in biodegradable polylactide-co-glycolide NPs, which were surface-modified with PGON. Fluorescent-PGON-NPs were incubated with bladder cancer cell lines and human urothelial tissues, and instilled into mouse bladders. To assess tissue penetration, cell uptake and internalization of the NPs, fluorescence microscopy, FACS analysis and NP tissue extraction were used.
Results: Uptake of C6-PGON-NPs, as measured by fluorescence intensity, was increased ten-fold compared to non-surface modified C6-NPs in both human ureter and in intravesically instilled mouse bladder. C6-PGON-NPs were internalized in T-24 and UM-UC-3 bladder cancer cells to a greater extent, on average 20-40% greater than unmodified NPs. FACS demonstrated that C6-PGON-NPs were internalized into bladder cancer cells and NR-PGON-NPs were noted to penetrate through the lamina propria to the level of detrusor muscle in mouse bladder.
Conclusions: Fluorescent-PGON-NPs were highly internalized in human bladder cancer cell lines compared to unmodified NPs, and were able to penetrate into the lamina propria of urothelial tissues. These results suggest that surface-modified, drug-loaded NPs could potentially provide an effective local delivery system for both benign and malignant disease with the advantage of a decreased systemic side effect profile.


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