Effect of varying the molecular weight of the MR contrast agent Gd-DTPA-polylysine on blood pharmacokinetics and enhancement patterns

The effects of varying the molecular weight of gadolinium-DTPA (diethylenetriaminepentaacetic acid)—polylysine, a macromolecular magnetic resonance (MR) imaging contrast agent, on blood pharmacokinetics and dynamic tissue MR imaging signal enhancement characteristics were studied in normal rats. Blood elimination half-life, total blood clearance, volume of the central compartment (V_cc) and the steady-state distribution volume (V_ssd) were calculated for four Gd-DTPA-polylysine polymers with average molecular weights of 36, 43.9, 139, and 480 kd and compared with corresponding values for Gd-DTPA (0.57 kd) and Gd-DTPA-albumin (92 kd). Blood elimination half-life increased sevenfold with an increase in molecular weight from 36 to 480 kd. The V_cc values for all polylysine polymers did not differ significantly from the V_cc value for Gd-DTPA-albumin but were significantly smaller than the V_cc value for Gd-DTPA. The V_ssd value for Gd-DTPA did not differ significantly from the V_ssd value for the 36- and 43.9-kd polymers but was significantly larger than the V_ssd values for the 139-and 480-kd polymers and for Gd-DTPA-albumin. On T1-weighted coronal spin-echo MR images, dynamic signal enhancement profiles in liver and kidney for the 36-, 43.9-, and 480-kd Gd-DTPA-polylysine chelates corresponded to the blood pharma-cokinetic data. Increasing molecular weight of Gd-DTPA-polylysine formulations substantially slows blood clearance and produces a prolonged, almost constant tissue signal enhancement for the 60-minute observation period.     

Gd-DTPA-cascade-polymer: Potential blood pool contrast agent for MR imaging

Gadolinium-DTPA (diethylenetriaminepentaacetic acid)-cascade-polymer, a potential new blood pool contrast agent for magnetic resonance (MR) imaging, was compared with a known blood pool agent, Gd-DTPA-polylysine, in an animal model. The relative signal intensities of liver, renal cortex, pancreas, and trunk muscle were assessed in 12 pigs between 4 seconds and 120 minutes after injection of a 20 μmol/kg dose of each contrast agent, by using a FLASH (fast low-angle shot) sequence. Except for muscle, all tissues showed visible enhancement after injection of either contrast agent. After injection of Gd-DTPA-polymer, enhancement patterns in the liver, renal cortex, and pancreas were similar to those seen after injection of Gd-DTPA-polylysine. No statistically significant differences in enhancement between the two contrast agents were found at any time point. The authors conclude that the contrast kinetics of Gd-DTPA-cascade-polymer are similar to those of Gd-DTPA-polylysine and that this agent may also be used as a blood pool contrast agent for MR imaging.     

Evaluation of Gd-DTPA-labeled dextran as an intravascular MR contrast agent: imaging characteristics in normal rat tissues.

Dextran covalently linked to moieties of gadolinium diethylenetriamine pentaacetic acid (DTPA), for use as a macromolecular, intravascular blood pool marker for contrast material-enhanced magnetic resonance (MR) imaging was characterized by means of physicochemical and relaxivity measurements and MR imaging in healthy rats. Dextran labeled with 15 Gd-DTPA moities (molecular weight of approximately 75,000 d) had a T1 relaxivity at 0.25 T and 37 degrees C of 157.1 mmol-1.sec-1 per molecule and 10.5 mmol-1.sec-1 per gadolinium atom, more than twice that of unbound Gd-DTPA. Osmolality was 300-350 mOsm/kg at a gadolinium concentration of 0.01 mmol/L. Tissue enhancement was essentially linearly related to injected dose in the gadolinium dose range of 0.01-0.05 mmol/kg of body weight. Approximate typical enhancement values over baseline for normal tissues at 10 minutes after a gadolinium dose of 0.05 mmol/kg were as follows: cardiac muscle, adrenal gland, and liver, 40%-50%; lungs, 160%-200%; renal cortex, 130%; renal medulla, 240%; spleen, 75%; muscle, 15%; and brain, 5%-10%. Projection-subtraction images showed that dextran-(Gd-DTPA)15 remained intravascular for at least 1 hour after injection. The prolonged and easily appreciated levels of tissue enhancement with dextran-(Gd-DTPA)15, at a gadolinium dose less than that routinely used in Gd-DTPA, indicate further evaluation of this macromolecular marker.     

Hepatic metastases: liposomal Gd-DTPA-enhanced MR imaging

Liposomal gadolinium diethylenetriaminepentaacetic acid (DTPA) encapsulated within 70- and 400-nm vesicles was tested as a contrast agent for magnetic resonance (MR) imaging of the liver in rats with hepatic metastases. Liposomal Gd-DTPA caused significant improvement in contrast between liver and tumor (P less than .005) on T1-weighted MR images. Smaller 70-nm liposomal Gd-DTPA vesicles caused greater contrast enhancement, reflecting the larger surface-area-to-volume ratio of the smaller vesicles. Liposomal Gd-DTPA-enhanced images permitted significant improvement in metastasis detection by five blinded radiologists (P less than .005). By comparison, free Gd-DTPA without liposomes caused a statistically significant reduction in contrast between tumor and liver and reduced lesion detection (P less than .01). Liposomal Gd-DTPA also resulted in sustained vascular enhancement for 1 hour after administration. The results suggest that paramagnetic liposomes may become a useful MR imaging contrast agent.     

Prolonged positive contrast enhancement with Gd-EOB-DTPA in experimental liver tumors: Potential value in tissue characterization

To evaluate the potential of the hepatobiliary magnetic resonance (MR) imaging contrast agent gadolinium EOB-DTPA (ethoxybenzyl diethylenetria-minepentaacetic acid) for the characterization of hepatic tumors, 79 primary and six implanted hepatomas in 38 rats were studied. MR imaging findings after administration of Gd-DTPA (0.3 mmol/kg) and Gd-EOB-DTPA (30 μmol/kg) were correlated with microangiographic and histologic findings. Gd-EOB-DTPA produced a strong liver enhancement, which caused prompt negative contrast enhancement (CE) in all implanted hepatomas and in 77 of 79 primary hepatomas. A positive CE that lasted up to 2 hours was found in two of 79 primary hepatomas, both of which were highly differentiated (grade I) hepatocellular carcinomas (HCCs). The rest were moderately differentiated to undifferentiated HCCs (grades II-IV). Rim enhancement, which corresponded histologically to peritumoral malignant infiltration sequestering normal hepatocytes, was seen around all implanted and some primary hepatomas. Positive tumor CE after administration of Gd-EOB-DTPA in this study is much less frequent but much more specific in comparison with the results of previous studies with manganese-DPDP (N, N′-dipyridoxylethylenediamine-N,N′-diacetate 5,5′-bis[phosphate]). These findings may help further discriminate hepatic tumors.     

In vivo fluorine-19 MR imaging: Relaxation enhancement with Gd-DTPA

The lack of a naturally occurring background signal from fluorine in magnetic resonance (MR) imaging makes fluorinated compounds potentially attractive candidates for tissue-specific MR contrast agents. Problems associated with the in vivo use of fluorinated compounds are toxicity, which limits the amount of agent that can be used; multiple resonance lines; and an excessively long T1, which leads to long sequence TRs and consequently long imaging times. Many fluorinated agents also possess complex MR spectra that result in chemical shift artifacts if not corrected. The authors demonstrate the use of an extracellular fluorinated agent with a single MR peak for selective imaging of a brain abscess in an animal model and show that the image signal per unit of acquisition time can be enhanced through the use of a T1 relaxation agent, gadolinium diethylenetriamine-pentaacetic acid (DTPA). Trifluoromethylsulfonate was administered at a fluorine-19 dose of 4 mmol/kg, and fluorine images of the induced abscess were acquired before and after the injection of a standard dose of Gd-DTPA (0.1 mmol/kg); non—section-selected projection images were used. Typical imaging times were less than 5 minutes. The signal enhancement factor achieved was approximately four (4.0 ± 0.8) with use of a 500/12 (TR msec/TE msec) spinecho sequence.     

Contrast-enhanced MRI of tumors. Comparison of Gd-DTPA and a macromolecular agent

The study aim was to define potential differences and advantages in magnetic resonance (MR) patterns of tumoral contrast enhancement using either a small molecular, extracellular fluid contrast enhancer [Gd-DTPA] or a macromolecular agent [albumin-(Gd-DTPA)20], designed for primary intravascular biodistribution. MR images of 25 mice with implanted fibrosarcomas were obtained before and repeatedly for up to 120 minutes after injection of either Gd-DTPA [0.2 mmol/kg, n = 11] or albumin-(Gd-DTPA) [0.0029 mmol/kg, n = 14]. Histologically, this hypovascular tumor contained zones of viable tissue and non-viable, necrotic tissue. Using either type of contrast media, the viable portions enhanced strongly, up to 152% and the necrotic portions enhanced poorly, less than 31%. However, the time-course of enhancement differed between contrast agents. Gd-DTPA tended to provide maximal enhancement soon after administration with no significant changes over two hours. Enhancement from albumin-(Gd-DTPA) was weak initially, corresponding to tumor hypovascularity, but over two hours the signal of the viable tumor zones progressively increased in intensity. This gradual tumoral accumulation of the macromolecular agent within the tumor was considered to reflect abnormal capillary permeability, associated with neovascularity. Thus, the increasing intensity within the neoplastic tissues over time, reflecting abnormal capillary permeability for macromolecules, may serve as a useful, albeit indirect, marker of neoplasia.     

Preliminary clinical trial of gadodiamide injection: a new nonionic gadolinium contrast agent for MR imaging.

The safety and efficacy of a newly developed intravenous formulation of the nonionic contrast agent gadolinium diethylenetriaminepentaacetic acid-bis(methylamide), formulated as gadodiamide injection, was investigated. In 30 patients who underwent spin-echo magnetic resonance (MR) imaging before and after contrast agent enhancement, the enhanced images had characteristics judged similar to those of images enhanced by means of available gadolinium compounds. In 15 patients, contrast agent administration was of major diagnostic help, either revealing lesions not apparent without enhancement or providing important lesion characterization. In 12 patients, the lack of abnormal enhancement patterns was important in excluding the presence of disease. In three patients, the contrast agent did not provide information additional to that obtained with the unenhanced T1- and T2-weighted images. No clinically significant changes were observed in vital signs, neurologic status, or laboratory results. The authors conclude that, in this limited series, gadodiamide injection proved to be a safe and useful MR imaging contrast agent for evaluation of the central nervous system and surrounding structures.     

MRI of acute myocardial ischemia: comparing a new contrast agent, Gd-DTPA-24-cascade-polymer, with Gd-DTPA

A new macromolecular contrast agent, gadolinium diethylenetriamine pentaacetic acid (Gd-DTPA)-24-cascade-polymer, was compared with Gd-DTPA for time-dependent delineation of acute myocardial ischemia. Acute myocardial ischemia was produced in 12 rats by occluding the anterior branch of the left coronary artery for 20-40 minutes. Dynamic spin-echo magnetic resonance imaging (MRI) was performed for 30 minutes after injection of Gd-DTPA (n = 6) or the cascade polymer (n = 6) using equimolar doses (0.1 mmol of Gd/kg). The contrast agent-induced changes in signal intensity (deltaSI) in normal and ischemic myocardium were observed. In normal myocardium, both contrast agents caused a sharp increase in deltaSI, followed by a decline to baseline values over the 30-minute period. Enhancement in the ischemic myocardium was attenuated. Gd-DTPA showed greater deltaSI in ischemic myocardium than the cascade polymer, which gave rise to virtually no enhancement. Significant differences (P<0.05) in signal enhancement between normal and ischemic myocardium persisted for only 6 minutes using Gd-DTPA but for 18 minutes with the cascade polymer. Use of Gd-DTPA-24-cascade-polymer extends the temporal window of dynamic contrast-enhanced MRI for the differentiation of ischemic and normal myocardium. Identification of the ischemic zone is easier with the cascade polymer, which demonstrates virtually no signal enhancement in this territory.     

Comparison of gadobenate dimeglumine and gadopentetate dimeglumine: a study of MR imaging and inductively coupled plasma atomic emission spectroscopy in rat brain tumors

BACKGROUND AND PURPOSE: After the advent of extracellular contrast media, hepatobiliary-specific gadolinium chelates were developed to improve the diagnostic value of MR imaging of the liver. Gadobenate dimeglumine (Gd-BOPTA) is a new paramagnetic contrast agent with partial biliary excretion that produces prolonged enhancement of liver parenchyma on T1-weighted images. However, whether Gd-BOPTA is useful as a contrast agent in central nervous system disease, particularly in brain tumors, is unclear. METHODS: The behavior of Gd-BOPTA as a brain tumor-selective contrast agent was compared with that of gadopentetate dimeglumine (Gd-DTPA), an MR contrast agent used in central nervous system disease, in a common dose of 0.1 mmol/kg. An MR imaging study of these two contrast agents was performed, and tissue concentrations were measured with inductively coupled plasma atomic emission spectroscopy (ICP-AES). RESULTS: Gd-BOPTA showed better MR imaging enhancement in brain tumors than did Gd-DTPA at every time course until 2 hours after administration and no enhancement in peritumoral tissue and normal brain. Corresponding results with ICP-AES showed significantly greater uptake of Gd-BOPTA in tumor samples than that in peritumoral tissue and normal brain 5 minutes after administration. Gadolinium was retained for a longer time in brain tumors when Gd-BOPTA rather than Gd-DTPA was administered. CONCLUSION: Gd-BOPTA is a useful contrast agent for MR imaging in brain tumors and possibly an effective absorption agent for neutron capture therapy.     

Selective enhancement of experimental rat brain tumors with Gd-TPPS

The synthetic metalloporphyrin gadolinium (III)-tetraphenylporphine sulfonate (TPPS) was successfully used as a contrast agent for in vivo magnetic resonance (MR) imaging of rat brain glioma. After injection of Gd-TPPS, the signal intensity of experimental rat brain glioma distinctly increased on T1-weighted MR images, an effect similar to that produced by the clinically applied MR imaging contrast agent gadolinium diethylenetriaminepentaacetic acid (DTPA). In contrast to other contrast agents studied (Gd-DTPA, manganese [III]-TPPS), Gd-TPPS produced hypointensity in glioma on T2-weighted images. The tumor-selective accumulation of paramagnetic Gd-TPPS in glioma shortened T1 by 53%, from 1,315 msec ± 199 to 628 msec ± 106, and T2 by 34%, from 86 msec ± 4 to 57 msec ± 5 (2 days after injection of 0.25 mmol/kg Gd-TPPS). The relaxation times of normal cortex, striaturn, corpus callosum, and temporal muscle were not significantly affected. As a result, gliomas appeared hyperintense on T1-weighted images and hypointense on T2-weighted images. Owing to the strong effect of Gd-TPPS on the T2 of glioma, normal brain tissue, tumor, and peritumorous edema could be distinguished on T2-weighted images alone.     

Use of superparamagnetic contrast media to suppress signal from flowing spins: Preliminary experience

The authors describe their preliminary experience with the use of superparamagnetic magnetic resonance (MR) imaging contrast media for suppression of signal from flowing blood. The goal of this work was to determine if a superparamagnetic contrast agent could successfully eliminate blood signal during cardiac-gated MR imaging, thereby eliminating or reducing flow artifacts associated with the complex and variable hemodynamics within the heart chambers. Imaging and data analysis were performed in 17 dogs subjected to experimental myocardial infarction as part of a parallel project. Six doses (0.2, 1, 2, 3.5, 4, 5, and 10 mg/kg) of AMI-25, an experimental contrast agent, were used in the study. Spin-echo imaging was performed immediately before and every 5 minutes (for an average of 25 minutes) after bolus injection of the contrast agent. Variations in the image signal-to-noise ratio relative to a baseline (before injection of contrast agent) image were assessed as a function of dose and time. Preliminary results suggest that a considerable reduction in blood flow artifacts and, hence, increases in image signal-tonoise ratio can be achieved at doses greater than or equal to 3.5 mg/kg, for approximately 20 minutes after injection. Doses equal to or less than 2 mg/kg and images obtained more than 20 minutes after injection (regardless of dose) did not reliably show hemodynamic artifact suppression.     

Interstitial MR and CT lymphography with Gd-dTPA-co-alpha,omega-diaminoPEG(1450) and Gd-dTPA-co-1,6-diaminohexane polymers: preliminary experience

RATIONALE AND OBJECTIVES: The authors assessed the efficacy of two gadolinium-based polymers used as lymphotrophic contrast media for computed tomography (CT) and magnetic resonance (MR) imaging. MATERIALS AND METHODS: Two gadolinium-based polymers, gadolinium diethylenetriaminepentaacetic acid (DTPA)-co-1,6-diaminohexane (NC 22181) and Gd-DTPA-co-alpha, omega-diamino-polyethylene glycol(1450) (NC-66368), were formulated at a concentration of 80 mmol/L gadolinium. Doses of 0.1, 0.25, 1.0, or 2.0 mL per paw were administered subcutaneously into the hindpaws of normal rabbits. Spin-echo T1-weighted MR imaging (1.5 T) of rabbit popliteal and iliac nodes was performed before and immediately, 10 minutes, 2-3 hours, and 24 hours after injection. CT was performed 2-3 hours after injection of the high doses only. RESULTS: MR imaging revealed prompt enhancement of the popliteal nodes with both polymers at doses of 0.25 mL and above. For doses of 1.0 mL or less per paw, nodal percentage enhancement was maximal at 2 hours and then declined at 24 hours. At the highest doses, however, a reservoir of subcutaneous contrast material remained at the injection site and resulted in peak enhancement at 24 hours. At CT, popliteal node enhancement was faintly visible 2-3 hours after the administration of NC 22181. At lower doses, no enhancement was appreciable at CT. CONCLUSION: At 80 mmol/L formulations, the two gadolinium-based polymers provide excellent popliteal nodal enhancement on MR images. In addition, high doses of one polymer (NC 22181) were sufficiently concentrated in popliteal nodes to be visible on CT scans. Thus, this agent may be useful for both CT and MR lymphography.     

Gadolinium-DTPA-dextran: a macromolecular MR blood pool contrast agent

RATIONALE AND OBJECTIVES: Magnetic resonance (MR) imaging blood pool agents offer numerous advantages for vascular and tumor imaging. The purpose of this study was to test gadolinium-diethylenetriaminepentaacetate-dextran ([Gd]DTPA-dextran) as a new water soluble macromolecular blood pool agent for MR imaging. MATERIALS AND METHODS: [Gd]DTPA-dextran (187 gadolinium atoms per dextran, molecular weight 165 kD, diameter 17.6 nm) was synthesized. Fifteen anesthetized New Zealand White rabbits with thigh VX2 tumors were scanned in a knee coil at 1.5T. Coronal 3D MR angiographic sequences were obtained before and at several time points up to 72 hours after the intravenous bolus injection of [Gd]DTPA-dextran providing gadolinium at either 0.05 (n = 4) or 0.1 mmol/kg (n = 8) or [Gd]DTPA-bismethylamide (BMA) providing gadolinium at 0.1 mmol/kg (n = 3). Time enhancement curves for aorta, cava, and tumor rim were compared by univariate General Linear Model. RESULTS: Contrast enhancement of cava and aorta relative to a water phantom were significantly greater at all time points after either dose of [Gd]DTPA-dextran than after [Gd]DTPA-BMA (P < 0.01). Tumor rim enhancement was less intense for either dose of [Gd]DTPA-dextran at peak than for [Gd]DTPA-BMA (P < 0.05). Tumor rim enhancement with both doses of [Gd]DTPA-dextran became equivalent to that of [Gd]DTPA-BMA at one hour and was greater at 24 hours (P < 0.05). CONCLUSION: [Gd]DTPA-dextran is a new macromolecular MR contrast agent that can be synthesized to carry a high density of gadolinium atoms without intra-molecular cross-linking. It provides significantly greater vascular residence time than a conventional gadolinium chelate and shows promise for MR blood pool imaging.     

Comparison of Gd-BOPTA with Gd-DTPA in MR imaging of rat liver

A new lipophilic compound, gadolinium benzyloxypropionictetraacetate (BOPTA), with a high rate of biliary excretion was assessed as a magnetic resonance (MR) hepatospecific contrast-enhancing agent and compared with Gd-DTPA (diethylenetriaminepentaacetic acid) in MR imaging of normal rats. T1-weighted spin-echo images obtained before and after administration of each contrast agent at doses of 0.25, 0.5, and 1.0 mmol/kg showed greater enhancement of the liver with Gd-BOPTA than with Gd-DTPA, with the advantage more evident at lower doses. Images obtained with an inversion recovery sequence at the null value of rat liver parenchyma after injection of 0.1- and 0.5-mmol/kg doses of the contrast agent provided better evidence of the greater and longer-lasting hepatic enhancement due to Gd-BOPTA when compared with that of Gd-DTPA. Gd-BOPTA is a potentially good contrast agent for obtaining prolonged enhancement of the liver, permitting studies during the long time needed to acquire conventional T1-weighted images.     

Magnetic resonance imaging enhancement of normal tissues and tumors using macromolecular Gd-based cascade polymer contrast agents: preclinical evaluations

OBJECTIVES: We sought to compare magnetic resonance imaging (MRI) enhancement using 4 novel macromolecular polyethyleneglycol (PEG)-based cascade-polymer gadolinium contrast agents (macromolecular contrast media) in normal soft tissues and a breast cancer model. MATERIALS AND METHODS: Four candidate PEG cascade polymers with effective molecular weights of 74, 82, 106, and 132 kDa, respectively, and T1-relaxivities of 8.1, 9.1, 9.7, and 10.0, respectively (at 2 Tesla and 37 degrees C in HEPES buffer), initially were used to characterize liver and kidney MRI-enhancement patterns in normal Sprague-Dawley rats (n = 4-5 per contrast agent). Kinetic analysis of dynamic MRI enhancement was used in 8 nude rats bearing MDA-MB 435 breast cancers to estimate fractional plasma volume and apparent endothelial leakiness (K) in tumors and muscle. RESULTS: Soft-tissue enhancement patterns followed closely the blood enhancement over the course of 30-50 minutes with estimated blood half-lives between 23 and 73 minutes, which varied with effective molecular weights. The 2 smaller compounds yielded measurable leaks in normal muscle [K = 204 and 56 microL/(min.100 cm), respectively], whereas the 2 larger molecules did not leak in muscle [K = 0 microL/(min.100 cm)]; however, MRI-assayed leakiness of tumor vessels with respect to those 2 larger macromolecular contrast media was 68 +/- 27 and 16 +/- 8 microL/(min.100 cm), respectively. CONCLUSIONS: Two relatively large (effective molecular weight >82 kDa) PEG-based cascade polymer contrast agents were well-suited for MRI quantification of tissue plasma volume and for differentiating leaky cancer microvessels from nonleaky normal vessels.     

Contrast-enhanced MR imaging of diffuse and focal splenic disease with use of magnetic starch microspheres

The diagnostic value of magnetic starch microspheres (MSM), a new superparamagnetic contrast agent, was studied in experimental models of diffuse and focal splenic disease in rats by means of ex vivo relaxometry and in vivo magnetic resonance (MR) imaging. Owing to small differences in unenhanced T1 and T2 values between diffuse lymphoma and normal spleen, MR imaging failed to distinguish tumor-bearing animals from control animals by signal-to-noise ratios (SNRs) obtained with T1- and T2-weighted spin-echo sequences. One hour after injection of 20 μmol/kg MSM, lymphomatous spleen showed significantly (P <.001) reduced enhancement relative to normal splenic tissue. As a result, animals with diffuse lymphoma (SNR: 10.3 ± 1.7) could be easily differentiated from control animals (SNR: 5.5 ± 0.6) on T2-weighted (TR msec/TE msec = 2,000/45) images. In focal splenic disease, MSM produced normal enhancement of nontumorous splenic tissue, whereas relaxation times of tumors were not different before and after contrast agent injection. On T2-weighted images (2,000/45), the tumor-spleen contrast-to-noise ratio increased from (4.8 ± 1.6 to 21.8 ± 1.9 +354%), improving conspicuity of splenic tumors. The results show that MSM-enhanced MR imaging improves the detection of diffuse and focal splenic disease.     

Characterization of a gadolinium-labeled cholesterol derivative as an organ-specific contrast agent for adrenal MR imaging

The purpose of the study was to determine if derivatization of cholesterol with a paramagnetic label could result in an organ-specific contrast agent for magnetic resonance imaging of the adrenal glands. Gadolinium-DO3A-labeled cholesterol was synthesized and the relaxivities in water and blood plasma determined at 0.47 T and 40°C. Organ distribution was measured at 2 (n = 2) and 24 (n = 2) hours after intravenous injection of a 50 μmol/kg dose of Gd-DO3A-cholesterol in rats weighing 220–240 g. T1-weighted spin-echo images were acquired at 2 T before and after injection of 50 μmol/kg Gd-DO3A-cholesterol (n = 2) and Gd-DTPA (diethylenetriaminepentaacetic acid)-albumin (n = 2). More than 99% of the Gd-DO3A-cholesterol was found to be protein bound in bovine serum. High T1 and T2 relaxivities were found in water and plasma. High tissue concentrations of Gd-DO3A-cholesterol were found only in adrenal glands and liver. At 24 hours, adrenal gadolinium concentrations were about 10 times higher than in blood. At 2 hours after injection of Gd-DO3A-cholesterol. enhancement was 162% in adrenal glands and 146% in liver. With Gd-DTPA-albumin, enhancement values were 57% and 56%. respectively.     

Enhancement effects of a hepatocyte receptor—specific MR contrast agent in an animal model

The enhancement characteristics of the liver and spleen produced by a hepatocyte-specific magnetic resonance imaging agent, an arabinogalactan-coated ultrasmall superparamagnetic iron oxide derivative, BMS 180550, were evaluated. Both heavily T1- and T2-weighted sequences were used. Imaging was performed in the farm pig model, as a function of contrast agent concentration (5, 10, and 20 μmol of iron per kilogram) and delay (immediate, 0.5, 2.5, 5.0, 7.5, and 9.0 hours) after bolus injection of BMS 180550. BMS 180550 provided excellent contrast enhancement characteristics by producing marked positive enhancement with T1-weighted sequences and marked negative enhancement with T2-weighted sequences. The T1-weighted enhancement immediately after contrast agent injection was of greater magnitude in the spleen (329% ± 83) than in the liver (66% ± 16). Postcontrast negative enhancement with T2-weighted sequences was largely hepatocyte specific at 5 and 10 μmol/kg but was also seen within the spleen at 20 μmol/kg. The authors discuss the possible mechanisms that produce these changes and conclude that 10 μmol/kg BMS 180550 is near the optimum dose for maximizing the enhancement properties of this agent with all sequences in the farm pig.     

二步法预定位技术对荷人肝癌裸鼠模型的MR免疫成像研究

目的利用生物素亲和素系统(biotin avidinsystem,BAS)的靶向定位效应和生物放大作用,提高MR分子免疫成像的敏感性。方法制备生物素化抗人肝癌细胞单克隆抗体HAb18并测定其生物素化程度及抗原结合活性。20只荷人肝细胞癌裸鼠分为3组,二步法预定位组8只,先静脉注射生物素化单克隆抗体600μg,24h后再给予钆喷替酸葡甲胺链霉亲和素(Gd DTPA streptavidin,Gd DTPA SA);HAb18单克隆抗体Gd DTPA组6只,经尾静脉注射Gd DTPA HAb18;Gd DTPA对照组6只,静脉注射Gd DTPA。对实验动物行MR扫描,测量SET1WI平扫及增强后10、30、60min及3、6、12、24、48h图像内肿瘤的信号强度,绘制信号强度时间曲线,并计算肿瘤强化率及对比度噪声比(contrast to noiseratio,CNR)。结果HAb18单克隆抗体经生物素化后,每个抗体分子平均可结合20个分子生物素,其抗原结合活性约为91%。二步法预定位组内,肿瘤信号强度缓慢升高,增强后第6小时,肿瘤的强化率、CNR达到最大值,与其他两组相比较差异有统计学意义。48h后,肿瘤的强化仍肉眼可辨。单克隆抗体组内,肿瘤表现为缓慢轻度强化,增强后24h的强化率达13.5%,肿瘤信号强度、CNR与平扫比较差异均有统计学意义(P值均<0.05)。Gd DTPA对照组内,肿瘤表现为快进快出特点的强化特点。结论二步法预定位技