Subconjunctival nano- and microparticles sustain retinal delivery of budesonide, a corticosteroid capable of inhibiting VEGF expression

Invest Ophthalmol Vis Sci. 2003 Mar;44(3):1192-201. doi: 10.1167/iovs.02-0791.

Abstract

Purpose: The purpose of this study was to determine whether budesonide inhibits expression of vascular endothelial growth factor (VEGF) in a retinal pigment epithelial cell line (ARPE-19) and to determine whether subconjunctivally administered budesonide nano- and microparticles sustain retinal drug levels.

Methods: The effect of budesonide (100 pM to 10 microM) on VEGF secretion, expression of VEGF mRNA, and cytotoxicity were determined in ARPE-19 cells by ELISA, RT-PCR, and a cell-viability assay, respectively. To determine the involvement of glucocorticoid receptor in the observed effects of budesonide, secretion and mRNA expression studies were also performed in the presence of a glucocorticoid receptor antagonist (RU486). DL-Polylactide (PLA) nano- and microparticles containing budesonide were prepared by a solvent evaporation technique, and the particles were characterized for size, morphology, encapsulation efficiency, and in vitro release. Budesonide-PLA nano- and microparticles were administered subconjunctivally to one eye of Sprague-Dawley rats and drug levels in the retina, vitreous, lens, and cornea of both eyes were determined at the end of 1, 7, and 14 days.

Results: At concentrations devoid of cytotoxicity, budesonide inhibited VEGF secretion as well as mRNA expression in ARPE-19 cells in a dose-dependent manner. RU486 treatment prevented budesonide-mediated inhibition of VEGF secretion and VEGF mRNA expression. Budesonide-PLA nano- (345 nm) and microparticles (3.6 microm), with an encapsulation efficiency of 65% and 99%, respectively, sustained budesonide release in vitro. After subconjunctival administration, both budesonide-PLA nano- and microparticles produced sustained budesonide levels in the retina and other ocular tissues.

Conclusions: Budesonide is capable of inhibiting VEGF expression through glucocorticoid receptor activity. Subconjunctivally administered budesonide-PLA nano- and microparticles sustain retinal drug delivery.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / pharmacokinetics
  • Anti-Inflammatory Agents / pharmacology*
  • Biological Availability
  • Budesonide / pharmacokinetics
  • Budesonide / pharmacology*
  • Cell Line
  • Chromatography, High Pressure Liquid
  • Conjunctiva
  • Delayed-Action Preparations
  • Endothelial Growth Factors / genetics
  • Endothelial Growth Factors / metabolism*
  • Enzyme-Linked Immunosorbent Assay
  • Hormone Antagonists / pharmacology
  • Intercellular Signaling Peptides and Proteins / genetics
  • Intercellular Signaling Peptides and Proteins / metabolism*
  • Lymphokines / genetics
  • Lymphokines / metabolism*
  • Microspheres
  • Mifepristone / pharmacology
  • Particle Size
  • Pigment Epithelium of Eye / drug effects*
  • Pigment Epithelium of Eye / metabolism
  • Polyesters
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Retina / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tissue Distribution
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors

Substances

  • Anti-Inflammatory Agents
  • Delayed-Action Preparations
  • Endothelial Growth Factors
  • Hormone Antagonists
  • Intercellular Signaling Peptides and Proteins
  • Lymphokines
  • Polyesters
  • RNA, Messenger
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors
  • Mifepristone
  • poly(lactide)
  • Budesonide