Subconjunctival dendrimer-drug therapy for the treatment of dry eye in a rabbit model of induced autoimmune dacryoadenitis

Research output: Contribution to journalArticle

Abstract

Purpose: To investigate the efficacy of a single subconjunctival injection of dendrimer-dexamethasone conjugate in a rabbit model of induced autoimmune dacryoadenitis (AID). Methods: Dendrimer biodistribution after subconjunctival injection in AID animals was evaluated using Cy5-labelled dendrimer (D-Cy5) and confocal microscopy. Diseased animals were treated with free dexamethasone (Free-Dex), dendrimer-dexamethasone (D-Dex), or saline via a single subconjunctival injection. The efficacy was evaluated using various clinical evaluations, such as Schirmer's test, tear breakup time (TBUT), and fluorescein and rose Bengal staining. Histopathology was evaluated by H&E staining and immunostaining. Levels of inflammatory cytokines and aquaporin proteins in the LGs were determined by real-time PCR. Results: Subconjunctivally administered dendrimers selectively localized in the inflamed LGs, and were taken up by the infiltrating cells. At two weeks post single dose-treatment, the D-Dex group showed improved clinical evaluations. No significant changes were observed in other groups. H&E staining demonstrated less inflammatory cell infiltration and fewer atrophic acini in D-Dex group, compared to those treated with saline or Free-Dex. Immunohistochemistry demonstrated that the intensity of CD-18 (+) and RTLA (+) was weaker in LGs in the D-Dex group than in other treatment groups. Pro-inflammatory gene expression levels of MMP9, IL6, IL8, and TNFα were significantly decreased in the D-Dex group compared to the Free-Dex and saline group. Conclusions: The dendrimer exhibits pathology-dependent biodistribution in the inflamed LGs. Subconjunctivally administered D-Dex suppressed LG inflammation, leading to partial recovery of LG function with clinical improvement in induced AID. Sjögren's patients may benefit from this targeted nanomedicine approach.

Original languageEnglish (US)
JournalOcular Surface
DOIs
StateAccepted/In press - Jan 1 2018

Fingerprint

Dacryocystitis
Dendrimers
Dexamethasone
Rabbits
Drug Therapy
Therapeutics
Staining and Labeling
Injections
Nanomedicine
Rose Bengal
Aquaporins
Animal Diseases
Recovery of Function
Fluorescein
Tears
Interleukin-8
Confocal Microscopy
Real-Time Polymerase Chain Reaction
Interleukin-6

Keywords

  • Autoimmune dacryoadenitis
  • Dendrimer
  • Dexamethasone
  • Dry eye
  • Sjögren's syndrome
  • Subconjunctival injection

ASJC Scopus subject areas

  • Ophthalmology

Cite this

@article{0592c9c612444a3994ed8e60a251edc2,
title = "Subconjunctival dendrimer-drug therapy for the treatment of dry eye in a rabbit model of induced autoimmune dacryoadenitis",
abstract = "Purpose: To investigate the efficacy of a single subconjunctival injection of dendrimer-dexamethasone conjugate in a rabbit model of induced autoimmune dacryoadenitis (AID). Methods: Dendrimer biodistribution after subconjunctival injection in AID animals was evaluated using Cy5-labelled dendrimer (D-Cy5) and confocal microscopy. Diseased animals were treated with free dexamethasone (Free-Dex), dendrimer-dexamethasone (D-Dex), or saline via a single subconjunctival injection. The efficacy was evaluated using various clinical evaluations, such as Schirmer's test, tear breakup time (TBUT), and fluorescein and rose Bengal staining. Histopathology was evaluated by H&E staining and immunostaining. Levels of inflammatory cytokines and aquaporin proteins in the LGs were determined by real-time PCR. Results: Subconjunctivally administered dendrimers selectively localized in the inflamed LGs, and were taken up by the infiltrating cells. At two weeks post single dose-treatment, the D-Dex group showed improved clinical evaluations. No significant changes were observed in other groups. H&E staining demonstrated less inflammatory cell infiltration and fewer atrophic acini in D-Dex group, compared to those treated with saline or Free-Dex. Immunohistochemistry demonstrated that the intensity of CD-18 (+) and RTLA (+) was weaker in LGs in the D-Dex group than in other treatment groups. Pro-inflammatory gene expression levels of MMP9, IL6, IL8, and TNFα were significantly decreased in the D-Dex group compared to the Free-Dex and saline group. Conclusions: The dendrimer exhibits pathology-dependent biodistribution in the inflamed LGs. Subconjunctivally administered D-Dex suppressed LG inflammation, leading to partial recovery of LG function with clinical improvement in induced AID. Sj{\"o}gren's patients may benefit from this targeted nanomedicine approach.",
keywords = "Autoimmune dacryoadenitis, Dendrimer, Dexamethasone, Dry eye, Sj{\"o}gren's syndrome, Subconjunctival injection",
author = "Hui Lin and Ying Liu and Kambhampati, {Siva Pramodh} and Hsu, {Chih Chien} and Kannan Rangaramanujam and Yiu, {Samuel Chi-Hung}",
year = "2018",
month = "1",
day = "1",
doi = "10.1016/j.jtos.2018.05.004",
language = "English (US)",
journal = "Ocular Surface",
issn = "1542-0124",
publisher = "Ethis Communications, Inc.",

}

TY - JOUR

T1 - Subconjunctival dendrimer-drug therapy for the treatment of dry eye in a rabbit model of induced autoimmune dacryoadenitis

AU - Lin, Hui

AU - Liu, Ying

AU - Kambhampati, Siva Pramodh

AU - Hsu, Chih Chien

AU - Rangaramanujam, Kannan

AU - Yiu, Samuel Chi-Hung

PY - 2018/1/1

Y1 - 2018/1/1

N2 - Purpose: To investigate the efficacy of a single subconjunctival injection of dendrimer-dexamethasone conjugate in a rabbit model of induced autoimmune dacryoadenitis (AID). Methods: Dendrimer biodistribution after subconjunctival injection in AID animals was evaluated using Cy5-labelled dendrimer (D-Cy5) and confocal microscopy. Diseased animals were treated with free dexamethasone (Free-Dex), dendrimer-dexamethasone (D-Dex), or saline via a single subconjunctival injection. The efficacy was evaluated using various clinical evaluations, such as Schirmer's test, tear breakup time (TBUT), and fluorescein and rose Bengal staining. Histopathology was evaluated by H&E staining and immunostaining. Levels of inflammatory cytokines and aquaporin proteins in the LGs were determined by real-time PCR. Results: Subconjunctivally administered dendrimers selectively localized in the inflamed LGs, and were taken up by the infiltrating cells. At two weeks post single dose-treatment, the D-Dex group showed improved clinical evaluations. No significant changes were observed in other groups. H&E staining demonstrated less inflammatory cell infiltration and fewer atrophic acini in D-Dex group, compared to those treated with saline or Free-Dex. Immunohistochemistry demonstrated that the intensity of CD-18 (+) and RTLA (+) was weaker in LGs in the D-Dex group than in other treatment groups. Pro-inflammatory gene expression levels of MMP9, IL6, IL8, and TNFα were significantly decreased in the D-Dex group compared to the Free-Dex and saline group. Conclusions: The dendrimer exhibits pathology-dependent biodistribution in the inflamed LGs. Subconjunctivally administered D-Dex suppressed LG inflammation, leading to partial recovery of LG function with clinical improvement in induced AID. Sjögren's patients may benefit from this targeted nanomedicine approach.

AB - Purpose: To investigate the efficacy of a single subconjunctival injection of dendrimer-dexamethasone conjugate in a rabbit model of induced autoimmune dacryoadenitis (AID). Methods: Dendrimer biodistribution after subconjunctival injection in AID animals was evaluated using Cy5-labelled dendrimer (D-Cy5) and confocal microscopy. Diseased animals were treated with free dexamethasone (Free-Dex), dendrimer-dexamethasone (D-Dex), or saline via a single subconjunctival injection. The efficacy was evaluated using various clinical evaluations, such as Schirmer's test, tear breakup time (TBUT), and fluorescein and rose Bengal staining. Histopathology was evaluated by H&E staining and immunostaining. Levels of inflammatory cytokines and aquaporin proteins in the LGs were determined by real-time PCR. Results: Subconjunctivally administered dendrimers selectively localized in the inflamed LGs, and were taken up by the infiltrating cells. At two weeks post single dose-treatment, the D-Dex group showed improved clinical evaluations. No significant changes were observed in other groups. H&E staining demonstrated less inflammatory cell infiltration and fewer atrophic acini in D-Dex group, compared to those treated with saline or Free-Dex. Immunohistochemistry demonstrated that the intensity of CD-18 (+) and RTLA (+) was weaker in LGs in the D-Dex group than in other treatment groups. Pro-inflammatory gene expression levels of MMP9, IL6, IL8, and TNFα were significantly decreased in the D-Dex group compared to the Free-Dex and saline group. Conclusions: The dendrimer exhibits pathology-dependent biodistribution in the inflamed LGs. Subconjunctivally administered D-Dex suppressed LG inflammation, leading to partial recovery of LG function with clinical improvement in induced AID. Sjögren's patients may benefit from this targeted nanomedicine approach.

KW - Autoimmune dacryoadenitis

KW - Dendrimer

KW - Dexamethasone

KW - Dry eye

KW - Sjögren's syndrome

KW - Subconjunctival injection

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DO - 10.1016/j.jtos.2018.05.004

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