Pharmacokinetics and tumor disposition of PEGylated, methotrexate conjugated poly-l-lysine dendrimers

Kaminskas, Lisa M., Kelly, Brian D., McLeod, Victoria M., Boyd, Ben J., Krippner, Guy Y., Williams, Elizabeth D., & Porter, Christopher J. H. (2009) Pharmacokinetics and tumor disposition of PEGylated, methotrexate conjugated poly-l-lysine dendrimers. Molecular Pharmaceutics, 6(4), pp. 1190-1204.

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Abstract

Dendrimers have potential for delivering chemotherapeutic drugs to solid tumours via the enhanced permeation and retention (EPR) effect. The impact of conjugation of hydrophobic anticancer drugs to hydrophilic PEGylated dendrimer surfaces, however, has not been fully investigated. The current study has therefore characterised the effect on dendrimer disposition of conjugating α-carboxyl protected methotrexate (MTX) to a series of PEGylated 3H-labelled poly-L-lysine dendrimers ranging in size from generation 3 (G3) to 5 (G5) in rats. Dendrimers contained 50% surface PEG and 50% surface MTX. Conjugation of MTX generally increased plasma clearance when compared to conjugation with PEG alone. Conversely, increasing generation reduced clearance, increased metabolic stability and reduced renal elimination of the administered radiolabel. For constructs with molecular weights >20 kDa increasing the molecular weight of conjugated PEG also reduced clearance and enhanced metabolic stability but had only a minimal effect on renal elimination. Tissue distribution studies revealed retention of MTX conjugated smaller (G3-G4) PEG570 dendrimers (or their metabolic products) in the kidneys. In contrast, the larger G5 dendrimer was concentrated more in the liver and spleen. The G5 PEG1100 dendrimer was also shown to accumulate in solid Walker 256 and HT1080 tumours and comparative disposition data in both rats (1 to 2% dose/g in tumour) and mice (11% dose/g in tumour) are presented. The results of this study further illustrate the potential utility of biodegradable PEGylated poly-L-lysine dendrimers as long circulating vectors for the delivery and tumour-targeting of hydrophobic drugs.

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ID Code: 77751
Item Type: Journal Article
Refereed: Yes
Keywords: pharmacokinetics, tumor disposition, PEGylated, methotrexate conjugated poly-L-lysine dendrimers, molecular pharmaceutics, methotrexate/PEG-poly-L-lysine dendrimers
DOI: 10.1021/mp900049a
ISSN: 1543-8392
Subjects: Australian and New Zealand Standard Research Classification > MEDICAL AND HEALTH SCIENCES (110000) > ONCOLOGY AND CARCINOGENESIS (111200) > Cancer Cell Biology (111201)
Divisions: Current > Schools > School of Biomedical Sciences
Current > QUT Faculties and Divisions > Faculty of Health
Current > Institutes > Institute of Health and Biomedical Innovation
Copyright Owner: Copyright © 2009 American Chemical Society
Copyright Statement: This document is the Accepted Manuscript version of a Published Work that appeared in final form in
Molecular Pharmaceutics, copyright © American Chemical Society after peer review and technical editing by the publisher.
To access the final edited and published work see
http://pubs.acs.org/doi/abs/10.1021/mp900049a
Deposited On: 16 Oct 2014 06:04
Last Modified: 17 Oct 2014 08:57

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