Dendrimer-based targeted intravitreal therapy for sustained attenuation of neuroinflammation in retinal degeneration

Raymond Iezzi, Bharath R. Guru, Inna V. Glybina, Manoj K. Mishra, Alexander Kennedy, Rangaramanujam M. Kannan

Research output: Contribution to journalArticle

118 Citations (Scopus)

Abstract

Retinal neuroinflammation, mediated by activated microglia, plays a key role in the pathogenesis of photoreceptor and retinal pigment epithelial cell loss in age-related macular degeneration and retinitis pigmentosa. Targeted drug therapy for attenuation of neuroinflammation in the retina was explored using hydroxyl-terminated polyamidoamine (PAMAM) dendrimer-drug conjugate nanodevices. We show that, upon intravitreal administration, PAMAM dendrimers selectively localize within activated outer retinal microglia in two rat models of retinal degeneration, but not in the retina of healthy controls. This pathology-dependent biodistribution was exploited for drug delivery, by covalently conjugating fluocinolone acetonide to the dendrimer. The conjugate released the drug in a sustained manner over 90 days. In vivo efficacy was assessed using the Royal College of Surgeons (RCS) rat retinal degeneration model over a four-week period when peak retinal degeneration occurs. One intravitreal injection of 1 μg of FA conjugated to 7 μg of the dendrimer was able to arrest retinal degeneration, preserve photoreceptor outer nuclear cell counts, and attenuate activated microglia, for an entire month. These studies suggest that PAMAM dendrimers (with no targeting ligands) have an intrinsic ability to selectively localize in activated microglia, and can deliver drugs inside these cells for a sustained period for the treatment of retinal neuroinflammation.

Original languageEnglish
Pages (from-to)979-988
Number of pages10
JournalBiomaterials
Volume33
Issue number3
DOIs
Publication statusPublished - 01-01-2012

Fingerprint

Dendrimers
Retinal Degeneration
Microglia
Pharmaceutical Preparations
Retina
Rats
Fluocinolone Acetonide
Drug therapy
Therapeutics
Intravitreal Injections
Retinitis Pigmentosa
Retinal Pigments
Macular Degeneration
Pathology
Drug delivery
Pigments
Hydroxyl Radical
Cell Count
Epithelial Cells
Ligands

All Science Journal Classification (ASJC) codes

  • Bioengineering
  • Ceramics and Composites
  • Biophysics
  • Biomaterials
  • Mechanics of Materials

Cite this

Iezzi, Raymond ; Guru, Bharath R. ; Glybina, Inna V. ; Mishra, Manoj K. ; Kennedy, Alexander ; Kannan, Rangaramanujam M. / Dendrimer-based targeted intravitreal therapy for sustained attenuation of neuroinflammation in retinal degeneration. In: Biomaterials. 2012 ; Vol. 33, No. 3. pp. 979-988.
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Dendrimer-based targeted intravitreal therapy for sustained attenuation of neuroinflammation in retinal degeneration. / Iezzi, Raymond; Guru, Bharath R.; Glybina, Inna V.; Mishra, Manoj K.; Kennedy, Alexander; Kannan, Rangaramanujam M.

In: Biomaterials, Vol. 33, No. 3, 01.01.2012, p. 979-988.

Research output: Contribution to journalArticle

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