A Comparison of the Pharmacokinetics and Pulmonary Lymphatic Exposure of a Generation 4 PEGylated Dendrimer Following Intravenous and Aerosol Administration to Rats and Sheep

Gemma M. Ryan, Robert J. Bischof, Perenlei Enkhbaatar, Victoria M. McLeod, Linda J. Chan, Seth A. Jones, David J. Owen, Christopher J H Porter, Lisa M. Kaminskas

    Research output: Contribution to journalArticle

    12 Citations (Scopus)

    Abstract

    Purpose: Cancer metastasis to pulmonary lymph nodes dictates the need to deliver chemotherapeutic and diagnostic agents to the lung and associated lymph nodes. Drug conjugation to dendrimer-based delivery systems has the potential to reduce toxicity, enhance lung retention and promote lymphatic distribution in rats. The current study therefore evaluated the pharmacokinetics and lung lymphatic exposure of a PEGylated dendrimer following inhaled administration. Methods: Plasma pharmacokinetics and disposition of a 22 kDa PEGylated dendrimer were compared after aerosol administration to rats and sheep. Lung-derived lymph could not be sampled in rats and so lymphatic transport of the dendrimer from the lung was assessed in sheep. Results: Higher plasma concentrations were achieved when dendrimer was administered to the lungs of rats as a liquid instillation when compared to an aerosol. Plasma pharmacokinetics were similar between sheep and rats, although some differences in disposition patterns were evident. Unexpectedly, less than 0.5% of the aerosol dose was recovered in pulmonary lymph. Conclusions: The data suggest that rats provide a relevant model for assessing the pharmacokinetics of inhaled macromolecules prior to evaluation in larger animals, but that the pulmonary lymphatics are unlikely to play a major role in the absorption of nanocarriers from the lungs.

    Original languageEnglish (US)
    Pages (from-to)510-525
    Number of pages16
    JournalPharmaceutical Research
    Volume33
    Issue number2
    DOIs
    StatePublished - Feb 1 2016

    Fingerprint

    Dendrimers
    Pharmacokinetics
    Aerosols
    Intravenous Administration
    Rats
    Sheep
    Lung
    Plasmas
    Lymph
    Macromolecules
    Lymph Nodes
    Toxicity
    Animals
    Liquids
    Pharmaceutical Preparations
    Neoplasm Metastasis

    Keywords

    • lymphatic
    • pharmacokinetics
    • pulmonary
    • rats
    • sheep

    ASJC Scopus subject areas

    • Pharmaceutical Science
    • Organic Chemistry
    • Molecular Medicine
    • Pharmacology (medical)
    • Biotechnology
    • Pharmacology

    Cite this

    A Comparison of the Pharmacokinetics and Pulmonary Lymphatic Exposure of a Generation 4 PEGylated Dendrimer Following Intravenous and Aerosol Administration to Rats and Sheep. / Ryan, Gemma M.; Bischof, Robert J.; Enkhbaatar, Perenlei; McLeod, Victoria M.; Chan, Linda J.; Jones, Seth A.; Owen, David J.; Porter, Christopher J H; Kaminskas, Lisa M.

    In: Pharmaceutical Research, Vol. 33, No. 2, 01.02.2016, p. 510-525.

    Research output: Contribution to journalArticle

    Ryan, Gemma M. ; Bischof, Robert J. ; Enkhbaatar, Perenlei ; McLeod, Victoria M. ; Chan, Linda J. ; Jones, Seth A. ; Owen, David J. ; Porter, Christopher J H ; Kaminskas, Lisa M. / A Comparison of the Pharmacokinetics and Pulmonary Lymphatic Exposure of a Generation 4 PEGylated Dendrimer Following Intravenous and Aerosol Administration to Rats and Sheep. In: Pharmaceutical Research. 2016 ; Vol. 33, No. 2. pp. 510-525.
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    abstract = "Purpose: Cancer metastasis to pulmonary lymph nodes dictates the need to deliver chemotherapeutic and diagnostic agents to the lung and associated lymph nodes. Drug conjugation to dendrimer-based delivery systems has the potential to reduce toxicity, enhance lung retention and promote lymphatic distribution in rats. The current study therefore evaluated the pharmacokinetics and lung lymphatic exposure of a PEGylated dendrimer following inhaled administration. Methods: Plasma pharmacokinetics and disposition of a 22 kDa PEGylated dendrimer were compared after aerosol administration to rats and sheep. Lung-derived lymph could not be sampled in rats and so lymphatic transport of the dendrimer from the lung was assessed in sheep. Results: Higher plasma concentrations were achieved when dendrimer was administered to the lungs of rats as a liquid instillation when compared to an aerosol. Plasma pharmacokinetics were similar between sheep and rats, although some differences in disposition patterns were evident. Unexpectedly, less than 0.5{\%} of the aerosol dose was recovered in pulmonary lymph. Conclusions: The data suggest that rats provide a relevant model for assessing the pharmacokinetics of inhaled macromolecules prior to evaluation in larger animals, but that the pulmonary lymphatics are unlikely to play a major role in the absorption of nanocarriers from the lungs.",
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