Kaori Togashi

Positive effects of polyethylene glycol conjugation to generation-4 polyamidoamine dendrimers as macromolecular MR contrast agents

Macromolecules conjugated with polyethylene glycol (PEG) acquire more hydrophilicity, resulting in a longer half‐life in circulation and lower immunogenicity. Two novel conjugates for MRI contrast agents were synthesized from a generation‐4 polyamidoamine dendrimer (G4D), 2‐(p‐isothiocyanatobenzyl)‐6‐methyl‐diethylenetriaminepentaacetic acid (1B4M), and one or two PEG molecules with a molecular weight of 20000 Da (PEG2‐G4D‐(1B4M‐Gd)62 (MW: 96 kD), PEG1‐G4D‐(1B4M‐Gd)63 (MW: 77 kD)). Their pharmacokinetics, excretion, and properties as vascular MRI contrast agents were evaluated and compared with those of G4D‐(1B4M‐Gd)64 (MW: 57 kD). PEG2‐G4D‐(1B4M‐Gd)62 remained in the blood significantly longer and accumulated significantly less in the liver and kidney than the other two preparations (P < 0.01). Although the blood clearance was slower, PEG2‐G4D‐(1B4M‐Gd)62 was excreted more readily without renal retention than the other two preparations. In conclusion, the positive effects of PEG conjugation on a macromolecular MRI contrast agent were found to be prolonged retention in the circulation, increased excretion, and decreased accumulation in the organs. Magn Reson Med 46:781–788, 2001.

Novel liver macromolecular MR contrast agent with a polypropylenimine diaminobutyl dendrimer core: Comparison to the vascular MR contrast agent with the polyamidoamine dendrimer core

As MRI contrast agents, more hydrophobic molecules reportedly accumulate in the liver and thus are potentially useful as liver MRI contrast agents. In this study, a generation‐4 polypropylenimine diaminobutane dendrimer (DAB‐Am64), which is expected to be more hydrophobic than the generation‐4 polyamidoamine dendrimer (PAMAM‐G4D), was used to synthesize a conjugate with 2‐(p‐isothiocyanatobenzyl)‐6‐methyl‐diethylenetriaminepentaacetic acid (1B4M) [DAB‐Am64‐(1B4M‐Gd)64] for complexing Gd(III) ions. This DAB conjugate quickly accumulated in the liver and its characteristics were studied and compared with those of a PAMAM conjugate [PAMAM‐G4D‐(1B4M‐Gd)64], which is known to be a useful vascular MRI contrast agent, in regard to its availability as a liver MRI contrast agent. DAB‐Am64‐(1B4M‐Gd)64 accumulated significantly more in the liver and less in blood than PAMAM‐G4D‐(1B4M‐Gd)64 (P < 0.001). Contrast‐enhanced MRI with DAB‐Am64‐(1B4M‐Gd)64 was able to homogeneously enhance liver parenchyma and visualize both portal and hepatic veins of 0.5 mm diameter in mice. In conclusion, DAB‐Am64‐(1B4M‐Gd)64 is a good candidate for a liver MRI contrast agent. Magn Reson Med 46:795–802, 2001.

Dynamic micro-MRI of liver micrometastasis with a novel liver macromolecular MR contrast agent DAB-Am64-(1B4M-Gd)64.

DAB-Am64-(1B4M-Gd)64 is a novel macromolecular liver MRI contrast agent consisting of a polypropylenimine diaminobutane (DAB) dendrimer conjugated with a bifunctional DTPA derivative complexing Gd(III) . The characteristics of DAB-Am64-(1B4M-Gd)64, including a rapid liver accumulation, have recently been reported. In this study, dynamic micro-MRI with DAB-Am64-(1B4MGd)64 was obtained in a liver metastasis-model in mice using colon carcinoma cells to evaluate visualization of micrometastatic tumors as compared to Gd-DTPA. The dynamic micro-MRI with DAB-Am64-(1B4M-Gd)64 was able to homogeneously enhance normal liver parenchyma and visualize micrometastatic tumors of 0.3 mm diameter in the liver of the mice with better contrast than with GdDTPA. In conclusion, DAB-Am64-(1B4M-Gd)64, a new liver MRI contrast agent, is potentially useful for diagnosis of liver micro-metastasis. The presence of hydrophobic groups on Gadolinium chelates can induce hepatocellular uptake and excretion into the bile ducts, gall bladder, and intestines, resulting in visualization of hyperintense/bright liver in a T1weighted image. This type of liver MRI contrast agents, containing Gadolinium and enhancing the signal of normal liver parenchyma, have actively been investigated for many years, and are currently in clinical use. The first Gadolinium-based agent of this class, [Gd(BOPTA)(H2O)] (MultiHance), has been approved in Europe. A related chelate, [Gd(EOB-DTPA)(H2O)] (Eovist), is currently in Phase III clinical trials. This agent is excreted to a greater extent via the liver, roughly 50% for [Gd(EOB-DTPA)(H2O)] versus 2-4% for [Gd(BOPTA)(H2O)] , resulting in significantly greater liver enhancement. DAB-Am64-(1B4M-Gd)64 was found to accumulate in the liver at approximately 50 % of the injected dose (%ID) within 15 min post-injection, and homogeneously enhanced the hepatic parenchyma [Kobayashi, Magn Reson Med 2001; 46: 795-802]. Thus, DAB-Am64-(1B4M-Gd)64 appears to be a comparable agent to [Gd(EOB-DTPA)(H2O)] . Herein, imaging of experimental liver micrometastases of LS174T tumors, which were not visualized by other imaging modalities in living animals, was studied using dynamic micro-MRI with DAB-Am64-(1B4M-Gd)64 to evaluate its imaging qualities as compared to Gd-DTPA. To the best of our knowledge, no study has been performed relating serial imaging of metastatic liver tumors in mice.