Biodegradable Film for the Targeted Delivery of siRNA-Loaded Nanoparticles to Vaginal Immune Cells

Mol Pharm. 2015 Aug 3;12(8):2889-903. doi: 10.1021/acs.molpharmaceut.5b00073. Epub 2015 Jul 6.

Abstract

The goal of this study was to develop and characterize a novel intravaginal film platform for targeted delivery of small interfering RNA (siRNA)-loaded nanoparticles (NP) to dendritic cells as a potential gene therapy for the prevention of sexually transmitted human immunodeficiency virus (HIV) infection. Poly(ethylene glycol) (PEG)-functionalized poly(D, L-lactic-co-glycolic acid) (PLGA)/polyethylenimine (PEI)/siRNA NP (siRNA-NP) were fabricated using a modified emulsion-solvent evaporation method and characterized for particle size, zeta potential, encapsulation efficiency (EE), and siRNA release. siRNA-NP were decorated with anti-HLA-DR antibody (siRNA-NP-Ab) for targeting delivery to HLA-DR+ dendritic cells (DCs) and homogeneously dispersed in a biodegradable film consisting of poly vinyl alcohol (PVA) and λ-carrageenan. The siRNA-NP-Ab-loaded film (siRNA-NP-Ab-film) was transparent, displayed suitable physicomechanical properties, and was noncytotoxic. Targeting activity was evaluated in a mucosal coculture model consisting of a vaginal epithelial monolayer (VK2/E6E7 cells) and differentiated KG-1 cells (HLA-DR+ DCs). siRNA-NP-Ab were rapidly released from the film and were able to penetrate the epithelial layer to be taken up by differentiated KG-1 cells. siRNA-NP-Ab demonstrated higher targeting activity and significantly higher knockdown of synaptosome-associated 23-kDa protein (SNAP-23) mRNA and protein when compared to siRNA-NP without antibody conjugation. Overall, these data suggest that our novel siRNA-NP-Ab-film may be a promising platform for preventing HIV infection within the female genital tract.

Keywords: SNAP-23; intravaginal delivery; microbicides; mucosal coculture model; polymeric film.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carrageenan / chemistry
  • Cell Differentiation
  • Cell Survival
  • Cells, Cultured
  • Dendritic Cells / cytology
  • Dendritic Cells / immunology*
  • Dendritic Cells / metabolism
  • Female
  • Genetic Therapy
  • HIV Infections / prevention & control
  • Humans
  • Lactic Acid / chemistry
  • Leukemia, Myeloid, Acute / genetics
  • Leukemia, Myeloid, Acute / immunology*
  • Leukemia, Myeloid, Acute / pathology
  • Nanoparticles / administration & dosage*
  • Nanoparticles / chemistry
  • Particle Size
  • Polyethylene Glycols / chemistry
  • Polyethyleneimine / chemistry
  • Polyglycolic Acid / chemistry
  • RNA, Small Interfering / genetics*
  • Synaptosomal-Associated Protein 25 / antagonists & inhibitors*
  • Synaptosomal-Associated Protein 25 / genetics
  • Vagina / cytology
  • Vagina / immunology*
  • Vagina / metabolism

Substances

  • RNA, Small Interfering
  • SNAP25 protein, human
  • Synaptosomal-Associated Protein 25
  • Polyglycolic Acid
  • Lactic Acid
  • Polyethylene Glycols
  • Carrageenan
  • Polyethyleneimine