Accumulation and cellular localization of nanoparticles in an ex vivo model of acute lung injury

Joshua C. Grimm, Fan Zhang, Jonathan T. Magruder, Todd C. Crawford, Manoj Mishra, Kannan M. Rangaramanujam, Ashish S. Shah

Research output: Contribution to journalArticle

Abstract

Background The benefit of nanomedicine in mitigating acute lung injury (ALI) is currently unknown. Therefore, we introduced the generation IV polyamidoamine dendrimers with neutral surface property (dendrimer) into our established ex vivo animal model and sought to determine their biodistribution to define their cellular uptake profile and to evaluate their potential as a drug delivery candidate for the treatment of ischemia–reperfusion–induced ALI. Methods Eight rabbit heart–lung blocks were harvested and exposed to 18 h of cold ischemia. The heart–lung blocks were then reperfused with rabbit donor blood. Dendrimer was conjugated to fluorescein isothiocyanate (D-FITC) for localization and quantification studies. D-FITC (30 mg or 150 mg) was injected into the bypass circuit and baseline, 1- and 2-h tissue samples were obtained to determine percent uptake. Low (10×) and high (40×) magnification images were obtained using confocal microscopy to confirm the accumulation and to determine the cellular targets of the dendrimer. Results Four heart–lung blocks were exposed to 30 mg and four to 150 mg of D-FITC. After adjusting for dry weight, the mean uptake in the 30 and 150 mg samples after 2 h of reperfusion were 0.79 ± 0.16% and 0.39 ± 0.22% of perfused doses, respectively. Confocal imaging demonstrated dendrimer uptake in epithelial cells and macrophages. Conclusions Fluorescently tagged dendrimers demonstrated injury-dependent tissue accumulation in a variety of different cell types. This unique approach will allow conjugation to and delivery of multiple agents with the potential of mitigating ALI injury while avoiding systemic toxicity.

Original languageEnglish (US)
Pages (from-to)78-85
Number of pages8
JournalJournal of Surgical Research
Volume210
DOIs
StatePublished - Apr 1 2017
Externally publishedYes

Fingerprint

Dendrimers
Acute Lung Injury
Nanoparticles
Heart Block
Fluorescein-5-isothiocyanate
Lung
Rabbits
Wounds and Injuries
Nanomedicine
Surface Properties
Blood Donors
Fluorescein
Confocal Microscopy
Ischemia
Epithelial Cells
Macrophages

Keywords

  • Acute lung injury
  • Animal model
  • Nanoparticle therapy

ASJC Scopus subject areas

  • Surgery

Cite this

Accumulation and cellular localization of nanoparticles in an ex vivo model of acute lung injury. / Grimm, Joshua C.; Zhang, Fan; Magruder, Jonathan T.; Crawford, Todd C.; Mishra, Manoj; Rangaramanujam, Kannan M.; Shah, Ashish S.

In: Journal of Surgical Research, Vol. 210, 01.04.2017, p. 78-85.

Research output: Contribution to journalArticle

Grimm, Joshua C.; Zhang, Fan; Magruder, Jonathan T.; Crawford, Todd C.; Mishra, Manoj; Rangaramanujam, Kannan M.; Shah, Ashish S. / Accumulation and cellular localization of nanoparticles in an ex vivo model of acute lung injury.

In: Journal of Surgical Research, Vol. 210, 01.04.2017, p. 78-85.

Research output: Contribution to journalArticle

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N2 - Background The benefit of nanomedicine in mitigating acute lung injury (ALI) is currently unknown. Therefore, we introduced the generation IV polyamidoamine dendrimers with neutral surface property (dendrimer) into our established ex vivo animal model and sought to determine their biodistribution to define their cellular uptake profile and to evaluate their potential as a drug delivery candidate for the treatment of ischemia–reperfusion–induced ALI. Methods Eight rabbit heart–lung blocks were harvested and exposed to 18 h of cold ischemia. The heart–lung blocks were then reperfused with rabbit donor blood. Dendrimer was conjugated to fluorescein isothiocyanate (D-FITC) for localization and quantification studies. D-FITC (30 mg or 150 mg) was injected into the bypass circuit and baseline, 1- and 2-h tissue samples were obtained to determine percent uptake. Low (10×) and high (40×) magnification images were obtained using confocal microscopy to confirm the accumulation and to determine the cellular targets of the dendrimer. Results Four heart–lung blocks were exposed to 30 mg and four to 150 mg of D-FITC. After adjusting for dry weight, the mean uptake in the 30 and 150 mg samples after 2 h of reperfusion were 0.79 ± 0.16% and 0.39 ± 0.22% of perfused doses, respectively. Confocal imaging demonstrated dendrimer uptake in epithelial cells and macrophages. Conclusions Fluorescently tagged dendrimers demonstrated injury-dependent tissue accumulation in a variety of different cell types. This unique approach will allow conjugation to and delivery of multiple agents with the potential of mitigating ALI injury while avoiding systemic toxicity.

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