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 () because of their fast rotation. Their typical values are in the range of 3–5 (mM·s) (2). Macromolecular Gd-chelates have been developed to improve the , 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 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 , whereas formation of complex micelles lowers the (1, 2, 6). In blood circulation, the agent presents as polymeric micelles, and the 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 . Thus the micelle agent exhibits changeable 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.