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. 2011 Dec;7(6):1001-8.
doi: 10.1016/j.nano.2011.03.007. Epub 2011 Apr 8.

Dendrimer-based MRI contrast agents: the effects of PEGylation on relaxivity and pharmacokinetics

Chie Kojima  1 , Baris Turkbey, Mikako Ogawa, Marcelino Bernardo, Celeste A S Regino, L Henry Bryant Jr, Peter L Choyke, Kenji Kono, Hisataka Kobayashi
Affiliations

Dendrimer-based MRI contrast agents: the effects of PEGylation on relaxivity and pharmacokinetics

Chie Kojima et al. Nanomedicine. 2011 Dec.

Abstract

Polyethylene glycol (PEG) surface modification can make nanomaterials highly hydrophilic, reducing their sequestration in the reticuloendothelial system. In this study, polyamidoamine (PAMAM) dendrimers bearing gadolinium (Gd) chelates were PEGylated with different PEG-chain lengths, and the effects on paramagnetic and pharmacokinetic properties were evaluated. Specifically, Gd chelate-bearing PAMAM dendrimers (generations 4 and 5; G4 and G5) were conjugated with two different PEG chains (2 kDa and 5 kDa; 2k and 5k). Long PEG chains (5k) on the smaller (G4) dendrimer resulted in reduced relaxivity compared to non-PEGylated dendrimers, whereas short PEG chains (2k) on a larger (G5) dendrimer produced relaxivities comparable to non-PEGylated G4 dendrimers. The relaxivity of all PEGylated or lysine-conjugated dendrimers increased at higher temperature, whereas that of intact G4 Gd-PAMAM dendrimer decreased. All PEGylated dendrimers had minimal liver and kidney uptake and remained in circulation for at least 1 hour. Thus, surface-PEGylated Gd-PAMAM dendrimers showed decreased plasma clearance and prolonged retention in the blood pool. Shorter PEG, higher generation conjugates led to higher relaxivity.

From the clinical editor: In this study, polyamidoamine dendrimers bearing gadolinium (Gd) chelates were PEGylated with different PEG-chain lengths, and the effects on paramagnetic and pharmacokinetic properties were evaluated.

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Figures

Figure 1
Figure 1
PEGylated dendrimers conjugated with Gd-DTPA via lysine. (A) PEG2k-PAMAM(G5), (B) PEG5k-PAMAM(G4), (C) PEG2k-PAMAM(G4) and (D) Ac-PAMAM (G4). The chemical structure of the surface modification is shown in panel (E).
Figure 2
Figure 2
T1-Relaxivity of PEG2k-PAMAM(G5) (circle), PEG5k-PAMAM(G4) (diamond), PEG2k-PAMAM(G4) (triangle), Ac-PAMAM (G4) (closed square). Gd-DTPA (cross) and PAMAM (G4) (open square) (A) Frequency dependency and (B) Temperature dependency.
Figure 3
Figure 3
T2-Relaxivity of PEG2k-PAMAM(G5) (circle), PEG5k-PAMAM(G4) (diamond), PEG2k-PAMAM(G4) (triangle), Ac-PAMAM (G4) (closed square). Gd-DTPA (cross) and PAMAM (G4) (open square). (A) Frequency dependency and (B) Temperature dependency.
Figure 4
Figure 4
3D MR images of the heart and large vessels (top) and kidneys (bottom) of mice injected with (A) PEG2k-PAMAM (G5), (B) PEG5k-PAMAM (G4), (C) PEG2k-PAMAM (G4) and (D) Ac-PAMAM (G4) at 1h after injection. Only Ac-PAMAM (G4) shows decreasing intensity from the heart and vessels and enhancement in the kidney parenchyma (arrows).
Figure 5
Figure 5
(A) Time-course of gadolinium concentration (mM) calculated from the T1 time in the jugular vein (A), kidney (B) and liver (C) of PEG2k-PAMAM(G5) (red), PEG5k-PAMAM(G4) (black), PEG2k-PAMAM(G4) (blue) and Ac-PAMAM (G4) (green). (D) Clearance rate (mMGd/min) from blood pool.
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