A Comparison of the Pharmacokinetics and Pulmonary Lymphatic Exposure of a Generation 4 PEGylated Dendrimer Following Intravenous and Aerosol Administration to Rats and Sheep
- 364 Downloads
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.
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.
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.
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.
KEY WORDSlymphatic pharmacokinetics pulmonary rats sheep
Bronchoalveolar lavage fluid
Caudal mediastinal lymph duct
Caudal mediastinal lymph node
Size exclusion chromatography
ACKNOWLEDGMENTS AND DISCLOSURES
This work was funded by a strategic Monash research grant and an Australian Research Council Linkage grant. LMK was supported by a NHMRC Career Development Fellowship (APP1022732). GMR was supported by a Cancer Council Victoria Postgraduate Scholarship.
- 7.Ryan GM, Kaminskas LM, Porter CJH. Nano-chemotherapeutics: Maximising lymphatic drug exposure to improve the treatment of lymph-metastatic cancers. J Control Release. 2014.Google Scholar
- 20.Meeusen EN, Snibson KJ, Hirst SJ, Bischof RJ. Sheep as a model species for the study and treatment of human asthma and other respiratory diseases. Drug Discov Today: Dis Model. 2009;6(4):101–6.Google Scholar
- 35.Protein purification: principles, high resolution methods, and applications. 3rd ed. Janson J-C, editor: Wiley; 2012.Google Scholar
- 40.Belvisi MG, Hele DJ. Animal models of cough. In: Chung FK, Boushey H, Widdicombe J, editors. Cough: causes, mechanisms and therapy: Wiley Online Library; 2007.Google Scholar
- 43.van der Wal JG, Meyer JHF. Protein digestion in ruminants. S Afr J Anim Sci. 1988;18(1):30–41.Google Scholar