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Polyion complex micelles of poly(ethylene glycol)-b-poly(L-lysine)-gadolinium-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-dextran sulfate

PIC micelles
, PhD
National Center for Biotechnology Information, NLM, NIH
Corresponding author.

Created: ; Last Update: June 23, 2011.

Chemical name:Polyion complex micelles of poly(ethylene glycol)-b-poly(L-lysine)-gadolinium-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-dextran sulfate
Abbreviated name:PIC micelles
Agent Category:Nanoparticles
Target Category:Non-targeted
Method of detection:Magnetic resonance imaging (MRI)
Source of signal / contrast:Gd
  • Checkbox In vitro
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No structure is available.



The polyion complex micelle of poly(ethylene glycol) (PEG)-b-poly(L-lysine) (P(Lys))-gadolinium-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (Gd-DOTA)-dextran sulfate, abbreviated as PIC micelles, 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 they are often synthesized with PEG, P(Lys), poly(glutamic acid), dendrimers, liposomes, or dextrans (3, 4). The large size of these macromolecular systems results in a higher r1 value because of the slow tumbling of macromolecules (5, 6). In animals, these macromolecular agents exhibit a long circulation time in the bloodstream and accumulate preferentially within tumors (7). 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 (1, 2, 6).

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, 6). 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, 2, 6). 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 from 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. A fully DOTA-substituted block copolymer forms polymeric micelles, whereas insufficient DOTA conjugation to lysine residues prevents the formation of a polymeric micelle (1, 6, 8). 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) (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 PIC (1, 6). In contrast to PEG-P(Lys-DOTA-Gd) micelles, PIC micelles are prepared from the amino groups of the lysine units and oppositely charged dextran sulfate (1). The pharmacokinetics and biodistribution of the PIC micelles can be controlled through adjustment of the ratios of dextran sulfates with different molecular weights. The PIC micelles accumulate in tumors and produce a significant enhancement on MRI. This chapter summarizes the data obtained with PIC micelles. Another chapter summarizes the data obtained with PEG-P(Lys-DOTA-Gd) micelles.



Shiraishi et al. described the synthesis of PIC micelles 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), and PIC micelles were formed by mixing PEG-P(Lys-DOTA-Gd) with a mixture of two dextran sulfates with different molecular weights (dex500k, 500 kDa; dex8k, 8 kDa). The dex500k/dex8k ratios were 1/2, 1/1, or 1/0.

In Vitro Studies: Testing in Cells and Tissues


Several PEG-P(Lys-DOTA-Gd) conjugates were synthesized, and in vitro characterization showed that one of the obtained PEG-P(Lys-DOTA-Gd) conjugates had 118 ethylene glycol units (molecular weight = 5,200), 65 lysine units, 13 DOTA conjugated to lysine residues, and 10 Gd ions, which was coded as 118-65-13-10. The other three PEG-P(Lys-DOTA-Gd) conjugates were similarly coded as 118-23-9-7, 118-23-23-7, and 272-22-10-8 (1).

The r1 values of all PEG-P(Lys-DOTA-Gd) conjugates were measured at 9.4 T (1). All of the obtained block copolymers exhibited a larger r1 value than that exhibited by Gd-DTPA. The r1 values ((mM·s)-1) were 3.7 for Gd-DTPA, 5.6 for 118-23-9-7, 6.1 for 118-65-13-10, 6.2 for 118-23-23-7, and 7.3 for 272-22-10-8. These results indicated that, to a certain extent, the chain length of PEG affected the r1 value.

The PIC micelles, produced by mixing various ratios of dex500k and dex8k, exhibited a diameter of 80–110 nm in cumulative size, near zero or slightly negative ζ-potentials, and 20%–30% decreases in r1 (4.4–4.7) (1).

In vitro MRI showed that 118-65-13-10 copolymers (no micelle formation) produced considerably higher signal intensity than that observed with Gd-DTPA. In contrast, the PIC micelles yielded clearly darker images than the parent block copolymers, confirming that formation of the PIC micelles lowered the signal intensity on T1-weighted images (1).

Animal Studies



Biodistribution studies in CDF1 female mice bearing colon 26 tumors (n = 3 mice/time point) showed that the distribution of PIC micelles depended on the dex500k/dex8k ratio (1). When the dex500k/dex8k ratio was 1/2 or 1/1, rapid clearance from kidneys was observed, indicating that the PIC micelles were not stable in blood for a long time. When PEG-P(Lys-DOTA-Gd) was mixed with dex500k only, higher accumulation in the liver and spleen was observed. In contrast, an equal ratio of dex500k and dex8k showed better tumor accumulation and lower accumulation in the liver and spleen. The PIC micelles had a better Gd concentration in blood over time than did Gd-DTPA as shown by studies of blood-concentration time course (n = 3 mice/time point per agent).

T1-Weighted gradient echo axial imaging was performed with the PIC micelles with a dex500k/dex8k ratio of 1/1 (n = 3 mice) (1). Signal enhancement (1.4 times) in the tumor area was observed at 24 h after injection of the agent.

Toxicity studies showed that, when the 118-65-13-10 block copolymer alone was intravenously injected into the mouse tail vein at a dose of 0.05 mmol Gd/kg, acute death of the injected mice (3 deaths of 3 injected mice) was observed within 120 min after injection (1). This is thought to result from the toxicity that is frequently observed for polycations. In contrast, this acute toxic death was not observed in the three mice injected with PIC micelles at the equivalent dose of Gd ions. The survival of injected mice was observed for up to 8 days without any unusual behavior. The body-weight loss was within 5%. This contrast in findings indicates that PIC micelle formation effectively reduced the toxicity. The in vivo toxicity of the cationic block copolymer was totally suppressed, at least in an acute phase, by micelle formation with a polyanion (1).

Other Non-Primate Mammals


No references are currently available.

Non-Human Primates


No references are currently available.

Human Studies


No references are currently available.


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]
Makowski M.R. et al. Molecular imaging with targeted contrast agents. Top Magn Reson Imaging. 2009;20(4):247–59. [PubMed: 20805735]
Torchilin V.P. Polymeric contrast agents for medical imaging. Curr Pharm Biotechnol. 2000;1(2):183–215. [PubMed: 11467336]
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]
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]
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]
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]
Nakamura E. et al. A polymeric micelle MRI contrast agent with changeable relaxivity. J Control Release. 2006;114(3):325–33. [PubMed: 16891027]


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