Impact of surface derivatization of poly-L-lysine dendrimers with anionic arylsulfonate or succinate groups on intravenous pharmacokinetics and disposition

Kaminskas, Lisa M., Boyd, Ben J., Karellas, Peter, Henderson, Scott A., Giannis, Michael P., Krippner, Guy Y. and Porter, Christopher J. H. (2007) Impact of surface derivatization of poly-L-lysine dendrimers with anionic arylsulfonate or succinate groups on intravenous pharmacokinetics and disposition. Molecular Pharmaceutics, 4 6: 949-961. doi:10.1021/mp070047s


Author Kaminskas, Lisa M.
Boyd, Ben J.
Karellas, Peter
Henderson, Scott A.
Giannis, Michael P.
Krippner, Guy Y.
Porter, Christopher J. H.
Title Impact of surface derivatization of poly-L-lysine dendrimers with anionic arylsulfonate or succinate groups on intravenous pharmacokinetics and disposition
Journal name Molecular Pharmaceutics   Check publisher's open access policy
ISSN 1543-8384
Publication date 2007-12-01
Year available 2007
Sub-type Article (original research)
DOI 10.1021/mp070047s
Open Access Status Not yet assessed
Volume 4
Issue 6
Start page 949
End page 961
Total pages 13
Place of publication Washington, DC, United States
Publisher American Chemical Society
Language eng
Formatted abstract
Tritium-labeled poly-l-lysine dendrimers displaying 8 or 16 surface lysines have been capped with benzene sulfonate (BS), benzene disulfonate (BDS), or succinate (Succ) groups, and the intravenous pharmacokinetics and disposition profiles of the resulting dendrimers (Lys8(BS)16, Lys16(BS)32, Lys16(BDS)32, Lys16(Succ)32) have been evaluated. Lys16(Succ)32 was rapidly removed from the plasma primarily via renal elimination. Lys16(BS)32 and Lys16(BDS)32 were opsonized, resulting in more prolonged plasma elimination kinetics and increased uptake by the liver. Data obtained at higher doses suggested some evidence of nonlinear pharmacokinetics. Lys8(BS)16 had reduced affinity for plasma proteins and was cleared more rapidly than the larger Lys16(BS)32 or Lys16(BDS)32 dendrimers. Lys8(BS)16 and Lys16(BS)32 were metabolized in vivo, resulting in the production of a low molecular weight species (possibly the cleavage product Lys(BS)2) that was extensively renally eliminated and accounted for almost all of the radioactivity recovered in urine (∼20–45% of administered 3H). In contrast, only 3–5% of the administered 3H was recovered in the urine of rats administered Lys16(BDS)32, suggesting increased resistance to in vivo degradation. The plasma clearance, distribution, and metabolic profiles of lysine dendrimers are therefore significantly influenced by the structure and charge of the capping groups. In particular, larger arylsulfonate-capped lysine dendrimers are rapidly opsonized and initially cleared from the plasma by the reticuloendothelial organs. The degree of metabolism is subsequently dictated by the nature of the surface capping group with BDS surfaces seemingly more resistant to breakdown. In contrast, smaller arylsulfonate-capped dendrimers are less readily opsonized and phagocytozed but are metabolically labile, and succinate-capped dendrimers are rapidly eliminated by the kidneys.
Keyword Arylsulfonate
Biodistribution
Dendrimer
Pharmacokinetics
Poly-L-lysine
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: School of Biomedical Sciences Publications
 
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