HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Buy All Versions of this Article: fj.09-129825v1 23/11/3752    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Sundaram, S. Articles by Kompella, U. B. PubMed PubMed Citation Articles by Sundaram, S. Articles by Kompella, U. B.

Surface-functionalized nanoparticles for targeted gene delivery across nasal respiratory epithelium

Sneha Sundaram^*,, Shyamal K. Roy^,, Balamurali K. Ambati^|| and Uday B. Kompella^*,,1

^* Department of Pharmaceutical Sciences,

Department of Obstetrics and Gynecology, and

Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, Nebraska, USA;

Department of Pharmaceutical Sciences, University of Colorado Denver, Denver, Colorado, USA; and

^|| Moran Eye Center, University of Utah, Salt Lake City, Utah, USA

¹ Correspondence: Department of Pharmaceutical Sciences, University of Colorado Denver, 12700 E. 19th Ave., Aurora, CO 80045, USA. E-mail: uday.kompella{at}ucdenver.edu

The objective of this study was to determine whether surface-modified nanoparticles enhance permeability across nasal mucosa, while retaining the effectiveness of the payload. The uptake and permeability of polystyrene nanoparticles (PS-NPs; FluoSpheres) was evaluated across the various regions of the bovine nasal epithelia following conjugation with deslorelin and transferrin. Uptake and transport of PS-NPs, deslorelin-PS-NPs, and transferrin-PS-NPs exhibited regional differences in the order: inferior turbinate posterior (ITP) > medium turbinate posterior (MTP) > medium turbinate anterior (MTA). Uptake and transport also exhibited directionality and temperature dependence in these tissues. Further, uptake as well as transport of functionalized nanoparticles could be inhibited by excess free functionalizing ligand. Confocal microscopy indicated the presence of functionalized nanoparticles in respiratory epithelial cells, as well as other cell types of the nasal tissue. We chose the ITP region for further studies with deslorelin or transferrin-conjugated poly-L-lactide-co-glycolide nanoparticles (PLGA-NPs) encapsulating an anti-VEGF intraceptor (Flt23k) plasmid. Transport of the nanoparticles, as well as the plasmid from the nanoparticles, exhibited the following order: transferrin-PLGA-NPs > deslorelin-PLGA-NPs > PLGA-NPs >> plasmid. The ability of the nanoparticles transported across the nasal tissue to retain the effectiveness of the Flt23k plasmid was evaluated by measuring transfection efficiency (percentage of cells expressing GFP) and VEGF inhibition in LNCaP and PC-3 prostate cancer cells. Transfection efficiencies and VEGF inhibition in LNCaP and PC-3 cells exhibited the following trend: transferrin-PLGA-NPs deslorelin-PLGA-NPs > PLGA-NPs >> plasmid. Further, functionalized nanoparticles exhibited transfection efficiencies and VEGF inhibition significantly superior compared with the routinely used transfecting agent, lipofectamine. Formulating plasmids into nanoparticulate delivery systems enhances the transnasal delivery and gene therapy at remote target cancer cells, which can be further enhanced by nanoparticle functionalization with deslorelin or transferrin.—Sundaram, S., Roy, S. K., Ambati, B. K., Kompella, U. B. Surface functionalized nanoparticles for targeted gene delivery across nasal respiratory epithelium.

Key Words: deslorelin • transferrin • anti-VEGF intraceptor • prostate cancer • gene therapy • poly-L-lactide-co-glycolide