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Poly(ethylene glycol)-b-poly(L-lysine)-gadolinium-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid micelle

PEG-P(Lys-DOTA-Gd)
, PhD
National Center for Biotechnology Information, NLM, NIH

Created: ; Last Update: June 23, 2011.

Chemical name:Poly(ethylene glycol)-b-poly(L-lysine)-gadolinium-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid micelle
Image PEGPLysDOTAGd.jpg
Abbreviated name:PEG-P(Lys-DOTA-Gd)
Synonym:
Agent Category:Nanoparticles
Target:Non-targeted
Target Category:Non-targeted
Method of detection:Magnetic resonance imaging (MRI)
Source of signal / contrast:Gd
Activation:No
Studies:
  • Checkbox In vitro
  • Checkbox Rodents
Structure of PEG-P(Lys-DOTA-Gd) (1).

Background

[PubMed]

Poly(ethylene glycol) (PEG)-b-poly(L-lysine) (P(Lys))-gadolinium-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (Gd-DOTA) micelle, abbreviated as PEG-P(Lys-DOTA-Gd), is a Gd-based macromolecular contrast agent that has been developed by Shiraishi et al. for contrast-enhanced magnetic resonance imaging (MRI) (1).

Magnetization recovery in the longitudinal direction (T1) and magnetization decay in the transverse plane (T2, T2*) form the basis of soft-tissue contrast in MRI (2). Use of Gd-based contrast agents results in a decrease of T1 and thus leads to positive contrast enhancement in MR images. However, to date, the US Food and Drug Administration-approved Gd-based agents such as Gd-diethylenetriamine pentaacetic acid (Gd-DTPA) are low-molecular-weight Gd-chelates that induce a relatively low T1 relaxivity (r1) because of their fast rotation. Their typical r1 values are in the range of 3–5 (mM·s)-1 (2). Macromolecular Gd-chelates have been developed to improve the r1, and are often synthesized with PEG, P(Lys), poly(glutamic acid), dendrimers, liposomes, or dextrans (3-5). The large size of these macromolecular systems results in a higher r1 value because of the slow tumbling of macromolecules. In animals, these macromolecular agents exhibit a long circulation time in the bloodstream and accumulate preferentially within tumors (6). However, agents with high molecular weights may fail to be excreted from the body, and a high blood concentration could result in undesirably high background (5).

Shiraishi et al. synthesized two types of polymeric micelle–based MRI contrast agents through conjugation of a PEG-P(Lys) block copolymer and a Gd-DOTA chelate (1, 5). One type possesses only DOTA-substituted lysine residues, and the other possesses both DOTA-substituted and unmodified lysine residues. These agents have been designed on the basis of the concept that stable Gd-chelated block copolymers produce a high r1, whereas formation of complex micelles lowers the r1 (1, 5, 7, 8). In blood circulation, the agent presents as polymeric micelles, and the r1 is suppressed to a low level. The micelle structure inhibits access of water molecules to Gd ions in the inner core of polymeric micelles. In contrast, the polymeric micelles are gradually dissociated into single-polymer chains at the tumor sites. Because water molecules can easily access the Gd ions, the accumulated single-polymer chains generate a higher r1. Thus the micelle agent exhibits changeable r1via the formation and dissociation of micelle structure. In addition, a single block copolymer with a molecular weight of <30,000 can be excreted via the kidneys, thus minimizing the potential toxicity of the agents.

The PEG-P(Lys-DOTA) system developed by Shiraishi et al. has multiple units of DOTA-bound lysine moiety (1, 5). A fully DOTA-substituted block copolymer forms polymeric micelles, whereas insufficient DOTA conjugation to lysine residues prevents the formation of a polymeric micelle. In other words, the micelle structures do not form in the presence of a small amount of unmodified lysine residue. The Gd ion is only partially chelated to DOTA (20% of vacant DOTA) in the block copolymer even excess amount of Gd ions was added to the block copolymer because DOTA–DOTA interactions prevent the Gd ion from freely chelating into a DOTA moiety. Gd-Chelated PEG-P(Lys-DOTA-Gd) could maintain the polymeric micelle structure. Therefore, the formation of the polymeric micelle appears to depend on interactions among vacant DOTAs. In addition, DOTA has been selected instead of DTPA because DOTA forms a more thermodynamically stable and kinetically inert complex than DTPA. The combination of PEG-P(Lys) copolymers and DOTA gives a more facile synthesis and a more stable metal chelation. Shiraishi et al. tested two micelle-based agents: PEG-P(Lys-DOTA-Gd) and PEG-P(Lys-DOTA-Gd)-dextran sulfate (PIC) micelles (1, 5). This chapter summarizes the data obtained with PEG-P(Lys-DOTA-Gd) micelles. Another chapter summarizes the data obtained with PIC micelles.

Synthesis

[PubMed]

Shiraishi et al. described the synthesis of PEG-P(Lys-DOTA-Gd) in detail (1). PEG-P(Lys-DOTA) was synthesized by means of polymerization of ε-(benzyloxycarbonyl)-L-lysine N-carboxyanhydride from PEG-NH2. The desired DOTA moiety numbers in PEG-P(Lys-DOTA) were controlled via adjustment of the DOTA-OSu/polymer ratio. Gd-Chelation was induced by mixing GdCl3·6H2O and PEG-P(Lys-DOTA) to produce PEG-P(Lys-DOTA-Gd).

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

In vitro characterization showed that the obtained PEG-P(Lys-DOTA-Gd) micelles had 118 ethylene glycol units, 17 lysine units, 17 DOTA conjugated to lysine residues, and 7 Gd ions, which was coded as 118-17-17-7 (1). This micelle had a weight average of 42.9 ± 7.6 nm, accompanied by a secondary aggregation of a weight average of 225.5 ± 53.0 nm. The size of the micelles was 50–250 nm in diameter. The zeta-potential was −9.55 mV in 150 mM NaCl solution, indicating that the polymeric micelle was negatively charged.

Animal Studies

Rodents

[PubMed]

Pharmacokinetic studies (n = 1 mouse) showed that accumulation of the PEG-P(Lys-DOTA-Gd) micelle remained at 22.5 ± 2.9% injected dose (ID) and 10.2 ± 1.4% ID (n = 3 blood samples) in blood at 24 h and 48 h after tail vein injection, respectively, indicating that the micelle was highly stable in blood (1). In contrast, the low-molecular-weight Gd-DTPA was immediately excreted 1 h after injection (only 1.4 ± 0.8% ID was found in blood).

Biodistribution of the PEG-P(Lys-DOTA-Gd) micelle was evaluated in CDF1 female mice bearing colon 26 tumors (1). Accumulation of the micelle in tumor tissues reached 6.1 ± 0.3% ID/g tissue at 24 h after injection. Low accumulation was also observed in heart, kidneys, and muscle tissue at the same time point. High accumulation was found in liver (10.8 ± 0.9% ID/g) and spleen (7.2 ± 0.7% ID/g) at 24 h after injection. In urine, 20.8 ± 7.6% ID of the polymeric micelle was found at 48 h after injection. The polymeric micelle was excreted through the kidney filtration in a dissociated polymer form.

T1-Weighted MR images before injection and 24 h after injection showed a clear signal enhancement (a two-fold increase) in the tumor compared with the signal before injection (1). The signal intensity in the tumor increased gradually by 24 h and then decreased slightly by 48 h. However, even at 24 h after the injection, an intense signal was observed in the heart and aorta areas. This suggests that a considerable amount of the contrast agent was circulating in the bloodstream. Apparent signal enhancement was also observed in the kidneys, indicating that the kidneys excreted the contrast agent. To estimate possible acute toxicity, a dose four times that of the original agent volume was injected into the mouse tail vein, and there was no significant difference for the body weight over 16 days in comparison to the control (less than ± 10%) (1).

Other Non-Primate Mammals

[PubMed]

No references are currently available.

Non-Human Primates

[PubMed]

No references are currently available.

Human Studies

[PubMed]

No references are currently available.

References

1.
Shiraishi K. et al. Preparation and in vivo imaging of PEG-poly(L-lysine)-based polymeric micelle MRI contrast agents. J Control Release. 2009;136(1):14–20. [PubMed: 19331861]
2.
Makowski M.R. et al. Molecular imaging with targeted contrast agents. Top Magn Reson Imaging. 2009;20(4):247–59. [PubMed: 20805735]
3.
Torchilin V.P. Polymeric contrast agents for medical imaging. Curr Pharm Biotechnol. 2000;1(2):183–215. [PubMed: 11467336]
4.
Torchilin V.P. PEG-based micelles as carriers of contrast agents for different imaging modalities. Adv Drug Deliv Rev. 2002;54(2):235–52. [PubMed: 11897148]
5.
Shiraishi K. et al. Polyion complex micelle MRI contrast agents from poly(ethylene glycol)-b-poly(l-lysine) block copolymers having Gd-DOTA; preparations and their control of T(1)-relaxivities and blood circulation characteristics. J Control Release. 2010;148(2):160–7. [PubMed: 20804796]
6.
Ma H. et al. Accelerated blood clearance was not induced for a gadolinium-containing PEG-poly(L-lysine)-based polymeric micelle in mice. Pharm Res. 2010;27(2):296–302. [PubMed: 20035375]
7.
Nakamura E. et al. A polymeric micelle MRI contrast agent with changeable relaxivity. J Control Release. 2006;114(3):325–33. [PubMed: 16891027]
8.
Bae Y., Kataoka K. Intelligent polymeric micelles from functional poly(ethylene glycol)-poly(amino acid) block copolymers. Adv Drug Deliv Rev. 2009;61(10):768–84. [PubMed: 19422866]
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