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

Abstract

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 R-carboxyl protected methotrexate (MTX) to a series of PEGylated 3 H-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) PEG 570 dendrimers (or their metabolic products) in the kidneys. In contrast, the larger G5 dendrimer was concentrated more in the liver and spleen. The G5 PEG 1100 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.

Systemic antiangiogenic activity of cationic poly-L-lysine dendrimer delays tumor growth

“…PEGylation has shown to prolong the blood circulation of dendrimers, such as polyester (22) and G 6 lysine dendrimers (23), improving tumor accumulation. Methotrexate (MTX) conjugated to PEGylated PLL dendrimers (G 5 , PEG1100) have also shown to accumulate in solid Walker 256 and HT-1080 tumors in rats and mice (24). However, no therapeutic efficacy was assessed in any of these studies.…”

Nanosized Drug Delivery Vectors and the Reticuloendothelial System

“…Therefore, nanomedicines circulating in the blood can be removed either via macrophages and lymphocytes in both the red and white pulp of the spleen. As an example, the biodistribution of polylysine dendrimers conjugated with both polyethylene glycol and methotrexate display more avid uptake into the spleen than in the liver of athymic nu/nu rats that have a reduced number of T cells (Kaminskas et al 2009a). Macrophages in the spleen likely act in this instance to compensate for the loss of T cell activity by becoming more phagocytically active.…”

Dendrimer Conjugates for Drug Delivery

“…C. J. Porter and coworkers described a less -versatile strategy to modify a series of PLL dendrimers, generations 3 to 5, with small dendrons based on succinimyldipropyldiamine that contain 50% of PEG (570 -2300 Da) and 50% of amide -linked MTX. 77 The release properties were not detailed, but tritium -labeled analogs allowed the pharmacokinetics and tumor uptake of these systems to be studied. As already observed with analogous dendrimeric systems, larger dendrimers or dendrimers with larger PEG chains presented an increased metabolic stability and decreased renal elimination, although small dendrimers with small PEG (570 Da) were extensively retained in liver because of specifi c folate -MTX interactions.…”