Pharmacokinetics and Tumor Disposition of PEGylated, Methotrexate Conjugated Poly-l-lysine Dendrimers

• Published in: Molecular pharmaceutics Vol. 6; no. 4; pp. 1190 - 1204
• Main Authors: Kaminskas, Lisa M, Kelly, Brian D, McLeod, Victoria M, Boyd, Ben J, Krippner, Guy Y, Williams, Elizabeth D, Porter, Christopher J. H
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 03-08-2009
• Subjects: Animals; Antimetabolites, Antineoplastic - blood; Antimetabolites, Antineoplastic - pharmacokinetics; Antimetabolites, Antineoplastic - urine; Carcinoma 256, Walker - metabolism; Carcinoma 256, Walker - pathology; Dendrimers - chemical synthesis; Dendrimers - pharmacokinetics; Drug Delivery Systems; Fibrosarcoma - metabolism; Fibrosarcoma - pathology; Kidney - drug effects; Metabolic Clearance Rate; Methotrexate - blood; Methotrexate - pharmacokinetics; Methotrexate - urine; Mice; Mice, SCID; Polyethylene Glycols - pharmacokinetics; Polylysine - pharmacokinetics; Rats; Rats, Nude; Rats, Sprague-Dawley; Tumor Cells, Cultured; drug targeting; poly-l-lysine; methotrexate; Dendrimer; tumor targeting; PEGylation
• ISSN: 1543-8384; 1543-8392
• DOI: 10.1021/mp900049a

Dendrimers have potential for delivering chemotherapeutic drugs to solid tumors 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 characterized the effect on dendrimer disposition of conjugating α-carboxyl protected methotrexate (MTX) to a series of PEGylated 3H-labeled 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 tumors, and comparative disposition data in both rats (1 to 2% dose/g in tumor) and mice (11% dose/g in tumor) 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 tumor-targeting of hydrophobic drugs.