Development of a macromolecular dual-modality MR-optical imaging for sentinel lymph node mapping

OBJECTIVE: To evaluate the effectiveness of a dual magnetic resonance-near infrared fluorescence optical imaging agent, poly(l-glutamic acid)-DTPA-Gd-NIR813, for both preoperative and intraoperative visualization and characterization of sentinel lymph nodes (SLN) in mice. MATERIALS AND METHODS: Poly(L-glutamic acid) was conjugated with DTPA-Gd and NIR813 dye to obtain PG-DTPA-Gd-NIR813. To confirm drainage into the SLNs, this agent was injected subcutaneously into the front paw of nude mice followed by isosulfan blue (n = 6). Furthermore, PG-DTPA-Gd-NIR813 was injected subcutaneously at doses of 0.002 mmol Gd/kg (4.8 nmol eq. NIR813) and 0.02 mmol Gd/kg (48 nmol eq. NIR813) (n = 3/dose). To differentiate metastatic from nonmetastatic lymph nodes, nude mice bearing human oral squamous cell carcinoma (DM14) were injected intralingually with 0.02 mmol Gd/kg PG-DTPA-Gd-NIR813 (n = 3). Pre- and postcontrast images were taken using 4.7 T Bruker MRI scanner and Xenogen optical imaging system. The status of lymph nodes resected under the guidance of optical imaging was confirmed by histologic examinations. RESULTS: PG-DTPA-Gd-NIR813 colocalized with isosulfan blue, indicating drainage to the SLN. After subcutaneous injection, axiliary and branchial lymph nodes were clearly visualized with both T1-weighted MR and optical imaging within 3 minutes of contrast injection, even at the lowest dose tested (0.002 mmol Gd/kg). After intralingual injection in tumor-bearing mice, MR imaging identified 4 of the 6 superficial cervical lymph nodes, whereas near-infrared fluorescence (NIRF) optical imaging identified all 6 cervical nodes. The pattern of contrast enhancement of SLN visualized in MR images showed a characteristic ring-shaped appearance with a central filling defect, possibly resulting from nodal infiltration of metastatic lesions. Histopathologic examination of the SLNs resected under NIRF imaging guidance revealed micrometastases in all 6 SLNs identified by NIRF imaging. CONCLUSIONS: The dual modality imaging method demonstrated in this study represents an effective technique for localization and characterization of SLN.     

Fluorescent bacterial magnetic nanoparticles as bimodal contrast agents

OBJECTIVES: The purpose of this study was to assess whether fluorochrome-coupled bacterial magnetic nanoparticles can be used as bimodal contrast agent for both magnetic resonance imaging (MRI) and near-infrared fluorescence optical (NIRF) imaging of cultured macrophages. MATERIALS AND METHODS: Bacterial magnetic nanoparticles (magnetosomes, particle diameter: 42 nm) were harvested from Magnetospirillum gryphiswaldense and characterized by using MRI. After covalent coupling to the fluorescent dye DY-676 (lambdaabs./lambdaem.= 676 nm/701 nm, Dyomics, Jena, Germany), the fluorescent magnetosomes were analyzed by fluorescence-activated cell sorting. Subsequently, murine macrophages J774 were incubated with the bimodal contrast agent (3 hours) and examined by a whole-body near infrared small animal imaging system as well as by using a 1.5 T clinical MR system. Moreover, labeled cells were characterized using confocal laser scanning microscopy (CLSM) and ultrathin section transmission electron microscopy. RESULTS: Characterization of the nanoparticles by MRI revealed R1 and R2 relaxivities of 3.2 mMs and 526 mMs, respectively. Fluorochrome-coupled magnetosomes exhibited increased fluorescence intensities at wavelengths >670 nm. Macrophages that were incubated with the contrast agent showed a significant fluorescence emission in the near infrared range as imaged with a whole body NIR imaging system, FACS analysis and CLSM. Moreover, CLSM data showed the greatest fluorescence intensities within intracellular compartments and colocalized with the magnetosomes. With MRI, both T1 and T2 relaxation times were substantially shortened at concentrations greater than 600 cells/microL. DISCUSSION AND CONCLUSION: Macrophages could be labeled with fluorescent magnetosomes, and they were successfully imaged using both a 1.5 T MR scanner as well as with NIRF optical methods. The use of this bimodal contrast agent for diagnostic purposes may benefit from the excellent spatial resolution of the MRI and the high sensitivity of the fluorescence imaging.     

Development of nanoparticle‐based magnetic resonance colonography

This study was to develop a novel method of nanoparticle‐based MR colonography. Two types of solid lipid nanoparticles (SLNs) were synthesized with loading of (a) gadolinium (Gd) diethylenetriaminepenta acetic acid to construct Gd‐SLNs as an MR T1 contrast agent and (b) otcadecylamine‐fluorescein‐isothiocyanate to construct Gd‐fluorescein isothiocyanate (FITC)‐SLNs for histologic confirmation of MR findings. Through an in vitro experiment, we first evaluated the size distribution and gadolinium diethylenetriaminepenta acetic acid entrapment efficiency of these SLNs. The SLNs displayed a size distribution of 50–300 nm and a gadolinium diethylenetriaminepenta acetic acid entrapment efficiency of 56%. For in vivo validation, 30 mice were divided into five groups, each of which was administered a transrectal enema using: (i) Gd‐SLNs (n = 6); (ii) Gd‐FITC‐SLNs (n = 6); (iii) blank SLNs (n = 6); (iv) gadolinium diethylenetriaminepenta acetic acid (n = 6); and (v) water (n = 6). T1‐weighted fluid‐attenuated inversion‐recovery MRI was then performed on mice after transrectal infusion of Gd‐SLNs or Gd‐FITC‐SLNs, which demonstrated bright enhancement of the colonic walls, with decrease in T1 relaxation time. When Gd‐FITC‐SLNs were delivered, green fluorescent spots were visualized in both the extracelluar space and the cytoplasm through colonic walls under confocal microscopy and fluorescence microscopy. This study establishes the “proof‐of‐principle” of a new imaging technique, called “nanoparticle‐based MR colonography,” which may provide a useful imaging tool for the diagnosis of colorectal diseases. Magn Reson Med, 2011. © 2010 Wiley‐Liss, Inc.     

Assessment of a potential tumor-seeking manganese metalloporphyrin contrast agent in a mouse model.

The performance of a newly developed potential tumor-seeking magnetic resonance (MR) contrast agent alpha-Aqua-13,17-bis(1-carboxypropionyl) carbamoylethyl-3,8-bis(1-phenethyloxyethyl)-beta-hydroxy-2,7,12,18-tetramethyl-porphyrinato manganese (III) (HOP-8P) was tested using a mouse model. Tumor-bearing (SCC-VII) mice were imaged using a 1.5T MR imager before and after intravenous administration of 0.1 mmol/kg of HOP-8P. A biodistribution analysis was performed using an optical emission spectrometer. Significant enhancement of the transplanted tumor was observed in MR images 24 h after intravenous injection of HOP-8P. The biodistribution assessment of manganese also correlated with the results of the imaging study. During the 24-h period following contrast administration, HOP-8P was consistently cleared from the circulation, liver, kidneys, and muscle; however, it was progressively accumulated within the tumor. HOP-8P is a promising tumor-seeking metalloporphyrin MR contrast agent with a wide imaging window.     

Cell tracking with gadophrin-2: a bifunctional contrast agent for MR imaging,optical imaging,and fluorescence microscopy

The purpose of this study was to assess the feasibility of use of gadophrin-2 to trace intravenously injected human hematopoietic cells in athymic mice, employing magnetic resonance (MR) imaging, optical imaging (OI), and fluorescence microscopy. Mononuclear peripheral blood cells from GCSF-primed patients were labeled with gadophrin-2 (Schering AG, Berlin, Germany), a paramagnetic and fluorescent metalloporphyrin, using established transfection techniques with cationic liposomes. The labeled cells were evaluated in vitro with electron microscopy and inductively coupled plasma atomic emission spectrometry. Then, 1×10⁶–3×10⁸ labeled cells were injected into 14 nude Balb/c mice and the in vivo cell distribution was evaluated with MR imaging and OI before and 4, 24, and 48 h after intravenous injection (p.i.). Five additional mice served as controls: three mice were untreated controls and two mice were investigated after injection of unlabeled cells. The contrast agent effect was determined quantitatively for MR imaging by calculating signal-to-noise-ratio (SNR) data. After completion of in vivo imaging studies, fluorescence microscopy of excised organs was performed. Intracellular cytoplasmatic uptake of gadophrin-2 was confirmed by electron microscopy. Spectrometry determined an uptake of 31.56 nmol Gd per 10⁶ cells. After intravenous injection, the distribution of gadophrin-2 labeled cells in nude mice could be visualized by MR, OI, and fluorescence microscopy. At 4 h p.i., the transplanted cells mainly distributed to lung, liver, and spleen, and 24 h p.i. they also distributed to the bone marrow. Fluorescence microscopy confirmed the distribution of gadophrin-2 labeled cells to these target organs. Gadophrin-2 is suited as a bifunctional contrast agent for MR imaging, OI, and fluorescence microscopy and may be used to combine the advantages of each individual imaging modality for in vivo tracking of intravenously injected hematopoietic cells.     

Contrast-enhanced near-infrared laser mammography with a prototype breast scanner: feasibility study with tissue phantoms and preliminary results of imaging experimental tumors

RATIONALE AND OBJECTIVES: Near-infrared (NIR) optical mammography without contrast has a low specificity. The application of optical contrast medium may improve the performance. The concentration-dependent detectability of a new NIR contrast medium was determined with a prototype optical breast scanner. In vivo imaging of experimental tumors was performed. METHODS: The NIR contrast agent NIR96010 is a newly synthesized, hydrophilic contrast agent for NIR mammography. A concentration-dependent contrast resolution was determined for tissue phantoms consisting of whole milk powder and gelatin. A central part of the phantoms measuring 2 x 2 cm2 without contrast was replaced with phantom material containing 1 micromol/L to 25 nmol/L NIR96010. The composite phantoms were measured with a prototype NIR breast scanner with lasers of lambda1 = 785 nm and lambda2 = 850 nm wavelength. Intensity profiles and standard deviations of the transmission signal in areas with and without contrast were determined by linear fit procedures. Signal-to-noise ratios and spatial resolution as a function of contrast concentration were determined. Near-infrared imaging of five tumor-bearing SCID mice (MX1 breast adenocarcinoma, tumor diameter 5-10 mm) was performed before and after intravenous application of 2 micromol/kg NIR96010. RESULTS: Spectrometry showed an absorption maximum of the contrast agent at 755 nm. No spectral shifts occurred in protein-containing solution. Signal-to-noise ratio in the transmission intensity profiles ranged from 1.1 at 25 nmol/L contrast to 28 at 1 micromol/L. At concentrations <40 nmol/L, no differentiation from the background was possible. The transitional area between the contrast-free edge of the phantom and the central contrast-containing part appeared in the profiles as a steep increase with a width of 4.2 +/- 1.8 mm. The experimental tumors were detectable in nonenhanced images as well as contrast-enhanced images, with better delineation after contrast administration. In postcontrast absorption profiles, a 44.1% +/- 11.3% greater absorption increase was seen in tumor tissue compared with normal tissue. CONCLUSIONS: The laser wavelength lambda1 of the prototype laser mammography device was not situated at maximum absorption of the contrast agent NIR96010 but on the descending shoulder of the absorption spectrum. This implies a 20% signal loss for contrast detection. Despite the nonideal measurement conditions, concentrations as low as 40 nmol/L were detectable in vitro. In vivo, all tumors were detectable in color-coded nonenhanced scans as well as in contrast-enhanced scans, with better delineation after contrast administration.     

Targeting of hematopoietic progenitor cells with MR contrast agents

PURPOSE: To label human hematopoietic progenitor cells with various magnetic resonance (MR) imaging contrast agents and to obtain 1.5-T MR images of them. MATERIALS AND METHODS: Hematopoietic progenitor cells, labeled with ferumoxides, ferumoxtran, magnetic polysaccharide nanoparticles-transferrin, P7228 liposomes, and gadopentetate dimeglumine liposomes underwent MR imaging with T1- and T2-weighted spin-echo and fast field-echo sequences. Data were analyzed by measuring MR signal intensities and R1 and R2* relaxation rates of labeled cells and nonlabeled control cells. Mean quantitative data for the various contrast agent groups were assessed for significant differences compared with control cells by means of the Scheffe test. As a standard of reference, MR imaging data were compared with electron microscopic and spectrometric data. RESULTS: For all contrast agents, intracellular cytoplasm uptake was demonstrated with electron microscopy and was quantified with spectrometry. When compared with nonlabeled control cells, progenitor cells labeled with iron oxides showed significantly (P <.05) increased R2*. Cells labeled with gadopentetate dimeglumine liposomes showed significantly increased R1. Detection thresholds were 5 x 10(5) cells for gadopentetate dimeglumine liposomes and ferumoxtran, 2.5 x 10(5) cells for ferumoxides and P7228 liposomes, and 1 x 10(5) cells for magnetic polysaccharide nanoparticles-transferrin. CONCLUSION: Hematopoietic progenitor cells can be labeled with MR contrast agents and can be depicted with a standard 1.5-T MR imager.     

Intraparenchymal brain metastases: MR imaging versus contrast-enhanced CT

Prospective and retrospective studies of 75 patients were performed to assess the sensitivities of magnetic resonance (MR) imaging and computed tomography (CT) in the evaluation of suspected intraparenchymal brain metastases. The findings on MR images were equivalent to those on CT scans in 49 of the 75 patients; the remaining findings were discordant in 26 patients, and neither MR imaging nor CT was consistently superior. MR imaging demonstrated more metastases in nine of these 26 patients. However, contrast material-enhanced CT scans were superior in lesion depiction in eight of the 26 patients. Large enhanced lesions that were nearly isointense on MR images were seen well on CT scans. In several cases in which results were discordant, gadolinium-diethylenetriaminepentaacetic acid (DTPA)-enhanced MR images were obtained, and this agent behaved similarly to iodinated contrast agents. If indicated clinically, such as before surgery for a single metastasis, the authors perform both MR imaging and contrast-enhanced CT. Gd-DTPA-enhanced MR imaging may prove to be the method of choice for depiction of intraparenchymal metastases.     

Dual optical and nuclear imaging in human melanoma xenografts using a single targeted imaging probe

INTRODUCTION: Dual-labeled imaging agents that allow both nuclear and optical imaging after a single injection would be advantageous in certain applications. In this study, we synthesized and characterized a dual-labeled RGD (Arg-Gly-Asp) peptide and compared nuclear and optical images obtained with this agent. METHODS: 111In-DTPA-Lys(IRDye800)-c(KRGDf) composed of both the 111In chelator diethylenetriaminepentaacetic acid (DTPA) and the near-infrared (NIR) fluorescent dye IRDye800 (excitation/emission, 765/792 nm) was synthesized. The probe was characterized with regard to in vitro biological activity and in vivo pharmacokinetics and the ability to target integrin alphavbeta3. Tumors of mice injected with the dual-labeled probe were imaged both by gamma scintigraphy and NIR fluorescence optical camera. RESULTS: DTPA-Lys(IRDye800)-c(KRGDf), DTPA-Lys-c(KRGDf) and c(KRGDf) inhibited the adhesion of melanoma M21 cells to vitronectin-coated surface with the similar biological activity. Both 111In-DTPA-Lys(IRDye800)-c(KRGDf) and 111In-DTPA-Lys-c(KRGDf) had significantly higher uptakes in alphavbeta3-positive M21 melanoma than in alphavbeta3-negative M21-L melanoma at 4-48 h after their injection. Side-by-side comparison of images obtained using 111In-DTPA-Lys(IRDye800)-c(KRGDf) revealed that in living mice, both optical imaging and gamma scintigraphy enabled noninvasive detection of the bound probe to alphavbeta3-positive tumors, with optical images providing improved resolution and sensitive detection of the superficial lesions and gamma images providing sensitive detection of deeper structures. CONCLUSION: The dual-labeled imaging probe 111In-DTPA-Lys(IRDye800)-c(KRGDf) was found to specifically bind to alphavbeta3 in melanoma tumor cells. Employing both nuclear and optical imaging with a single imaging probe may facilitate translation of NIR fluorescence optical imaging into clinical applications.     

Real time in vivo non-invasive optical imaging using near-infrared fluorescent quantum dots

RATIONALE AND OBJECTIVE: Deep-tissue optical imaging is of particular interest, as the equipment costs are lower than for competing technologies such as MRI. For this purpose, the development of novel contrast agents with near-infrared (NIR) fluorescence is especially important. We report on the use of NIR semiconductor nanocrystals in deep-tissue in vivo optical imaging. MATERIALS AND METHODS: Semiconductor nanocrystals of CdMnTe/Hg were grown in aqueous solution and then coated with bovine serum albumin (BSA). The nanocrystals were approximately 5 nm in diameter and have a broad fluorescence peak in the NIR (770 nm). Nanocrystals were injected either subcutaneously or intravenously into athymic NCR NU/NU and C3H/HENCR MTV mice and then excited with a spatially broad 633 nm source; the resulting fluorescence was captured with a sensitive CCD camera. RESULTS: We have demonstrated that the nanocrystals are a useful angiographic contrast agent for vessels surrounding and penetrating a murine squamous cell carcinoma in a C3H mouse. Preliminary assessment of the depth of penetration for excitation and emission was done by imaging a beating mouse heart, both through an intact thorax and after a thoracotomy. The temporal resolution associated with imaging the nanocrystals in circulation has been addressed, and the blood clearance for this contrast agent has also been measured. CONCLUSIONS: There was no significant photobleaching or degradation of the nanocrystals after an hour of continuous excitation. The stability of the nanocrystals together with the time resolution of the optical detection makes them particularly attractive candidates for pharmacokinetic imaging studies.     

Noninvasive MR imaging-guided focal opening of the blood-brain barrier in rabbits

PURPOSE: To determine if focused ultrasound beams can be used to locally open the blood-brain barrier without damage to surrounding brain tissue and if magnetic resonance (MR) imaging can be used to monitor this procedure. MATERIALS AND METHODS: The brains of 18 rabbits were sonicated (pulsed sonication) in four to six locations, with temporal peak acoustic power ranging from 0.2 to 11.5 W. Prior to each sonication, a bolus of ultrasonographic (US) contrast agent was injected into the ear vein of the rabbit. A series of fast or spoiled gradient-echo MR images were obtained during the sonications to monitor the temperature elevation and potential tissue changes. Contrast material-enhanced MR images obtained minutes after sonications and repeated 1-48 hours later were used to depict blood-brain barrier opening. Whole brain histologic evaluation was performed. RESULTS: Opening of the blood-brain barrier was confirmed with detection of MR imaging contrast agent at the targeted locations. The lowest power levels used produced blood-brain barrier opening without damage to the surrounding neurons. Contrast enhancement correlated with the focal signal intensity changes in the magnitude fast spoiled gradient-echo MR images. CONCLUSION: The blood-brain barrier can be consistently opened with focused ultrasound exposures in the presence of a US contrast agent. MR imaging signal intensity changes may be useful in the detection of blood-brain barrier opening during sonication.     

Intracellular bimodal nanoparticles based on quantum dots for high‐field MRI at 21.1 T

Multimodal, biocompatible contrast agents for high magnetic field applications represent a new class of nanomaterials with significant potential for tracking of fluorescence and MR in vitro and vivo. Optimized for high‐field MR applications—including biomedical imaging at 21.1 T, the highest magnetic field available for MRI—these nanoparticles capitalize on the improved performance of chelated Dy³⁺ with increasing magnetic field coupled to a noncytotoxic Indium Phosphide/Zinc Sulfide (InP/ZnS) quantum dot that provides fluorescence detection, MR responsiveness, and payload delivery. By surface modifying the quantum dot with a cell‐penetrating peptide sequence coupled to an MR contrast agent, the bimodal nanomaterial functions as a self‐transfecting high‐field MR/optical contrast agent for nonspecific intracellular labeling. Fluorescent images confirm sequestration in perinuclear vesicles of labeled cells, with no apparent cytotoxicity. These techniques can be extended to impart cell selectivity or act as a delivery vehicle for genetic or pharmaceutical interventions. Magn Reson Med, 2010. © 2010 Wiley‐Liss, Inc.     

Troubleshooting Arterial-Phase MR Images of Gadoxetate Disodium-Enhanced Liver

Gadoxetate disodium is a widely used magnetic resonance (MR) contrast agent for liver MR imaging, and it provides both dynamic and hepatobiliary phase images. However, acquiring optimal arterial phase images at liver MR using gadoxetate disodium is more challenging than using conventional extracellular MR contrast agent because of the small volume administered, the gadolinium content of the agent, and the common occurrence of transient severe motion. In this article, we identify the challenges in obtaining high-quality arterial-phase images of gadoxetate disodium-enhanced liver MR imaging and present strategies for optimizing arterial-phase imaging based on the thorough review of recent research in this field.     

Dynamics of tumor imaging with Gd-DTPA—polyethylene glycol polymers: Dependence on molecular weight

Macromolecular contrast media offer potential advantages over freely diffusible agents in magnetic resonance (MR) imaging outside the central nervous system. To identify an optimum molecular weight for macromolecular contrast media, the authors studied a novel macromolecular contrast agent, gadolinium diethylenetriaminepentaacetic acid polyethylene glycol (DTPA-PEG), synthesized in seven polymer (average) molecular weights ranging from 10 to 83 kd. Twenty-eight rabbits bearing V2 carcinoma in thighs underwent T1-weighted spin-echo imaging before injection and 5–60 minutes and 24 hours after injection of the Gd-DTPA-PEG polymers or Gd-DTPA at a gadolinium dose of 0.1 mmol/kg. Tumor region-of-interest measurements were obtained at each time point to determine contrast enhancement dynamics. Blood-pool enhancement dynamics were observed for the Gd-DTPA-PEG polymers larger than 20 kd. Polymers smaller than 20 kd displayed dynamics similar to those of the freely diffusible agent Gd-DTPA. Above the 20 kd threshold, tumor enhancement was more rapid for smaller polymers. The authors conclude that the 21.9-kd Gd-DTPA-PEG polymer is best suited for clinical MR imaging.     

腰椎术后MR增强扫描的应用价值

目的 将ＭＲＩ和再次手术所见相对照,探讨钆喷替酸葡甲胺（Ｇd-ＤＴＰＡ）增强ＭＲＩ在鉴别术后瘢痕粘连和椎间盘疝复发的应用价值和准确性。方法 ２２例腰椎术后病人因症状复发再次行腰椎ＭＲＩ检查并接受第２次手术。所有病人都做Ｇd-ＤＴＰＡ增强前、后ＭＲ矢状面、轴面成像,９例病人获取 强图像。结果 ＭＲＩ诊断２２例病人的２７个腰椎平面硬膜前肿物,其中瘢痕结节６个,椎间盘９个,椎间盘上包裹瘢痕１２个平面。与手术     

Evaluation of the postoperative meniscus of the knee: a study comparing conventional arthrography, conventional MR imaging, MR arthrography with iodinated contrast material, and MR arthrography with gadolinium-based contrast material

Objective. To compare four imaging methods in the evaluation of the postoperative meniscus: conventional arthrography, conventional MR imaging, MR arthrography with iodinated contrast material, and MR arthrography with gadolinium-based contrast material. Design and patients. Thirty-three patients referred for knee MR examinations with a history of meniscal surgery were studied prospectively. At the first patient visit, conventional MR examination was followed by an MR arthrogram with gadolinium-based contrast material. At the second visit, a conventional arthrogram with iodinated contrast material was followed immediately by an MR examination. Imaging examinations were interpreted by a masked reader, and then compared with the results of repeat arthroscopic surgery in 12 patients. Results. The correct evaluation of the status of postoperative menisci was allowed in 12 of 13 patients (92%) by MR arthrography using gadolinium-based contrast agent, 10 of 13 patients (77%) by conventional MR examination, 9 of 12 patients (75%) by MR arthrography, and 7 of 12 patients (58%) by conventional arthrography. Conclusion. Intra-articular fluid is advantageous in the evaluation of patients with a suspected meniscal retear. MR arthrography with gadolinium-based contrast material is the most accurate imaging method for the diagnosis of meniscal retears. Received: 7 April 1999 Revision requested: 26 May 1999 Revision received: 17 June 1999 Accepted: 18 June 1999     

In vivo studies of Gd-DTPA-monoclonal antibody and gd-porphyrins: potential magnetic resonance imaging contrast agents for melanoma

New tumor-specific contrast agents for clinical imaging and therapy for cancer are required. To this end Gd-H (Gd-hematoporphyrin), Gd-TCP (Gd-tetra-carboranylmethoxyphenyl-porphyrin), Gd-DTPA-WM53, and Gd-DTPA-9.2.27 were synthesized and administered by systemic injection to nude mice with human melanoma (MM-138) xenografts. The biodistribution T1 relaxation times and magnetic resonance (MR) image signal enhancement of the contrast agents are presented for the first time and compared for each group of five mice. A change (20%) in T1 relaxation times of water in human melanoma tumor xenografts was revealed 24 hours after injection of the labeled immunoconjugate Gd-DTPA-9.2.27. The percent of injected antibody or gadolinium that localized to the tumor was measured by inductively coupled plasma atomic emission spectroscopy (ICP-AES) to be approximately 35%. A higher concentration of gadolinium was achieved compared with nonspecific compounds, indicating selective delivery of Gd-DTPA-9.2.27 to the melanoma xenografts. Porphyrin-based contrast agents (Gd-H and Gd-TCP) also showed significant uptake in melanomas. The uptake of Gd-TCP by the tumor was sufficient to deliver boron atoms into the tumor, making possible dual use for both MR imaging (MRI) and boron neutron capture therapy (BNCT). The linear relationship found between the paramagnetic contribution to the relaxation rates and contrast agent concentration allows quantitative studies of paramagnetic contrast agent uptake.     

Contrast-enhanced MR imaging of postoperative scars and VX2 carcinoma in rabbits: comparison of macromolecular contrast agent and gadopentetate dimeglumine

PURPOSE: To compare the magnetic resonance (MR) imaging enhancement patterns of a blood pool contrast agent, SH L 643A, with those of gadopentetate dimeglumine in postoperative scars and VX2 carcinomas in rabbits and to compare these enhancement patterns with microvessel density in pathologic specimens. MATERIALS AND METHODS: Eighteen rabbits with experimentally induced postoperative scars (n = 12) or VX2 carcinoma (n = 6) in the thighs underwent sequential MR imaging first with gadopentetate dimeglumine and then, 24 hours later, with SH L 643A. The enhancement ratios (ie, the ratios of postcontrast to precontrast signal intensity) and the microvessel densities of postoperative scars and VX2 carcinomas were assessed. Differences were tested for by using the Mann-Whitney U and Wilcoxon signed rank tests. RESULTS: In postoperative scars, enhancement ratios were consistently lower with injection of SH L 643A than with injection of gadopentetate dimeglumine for up to 30 minutes (P <.05). In postoperative scars, mean peak enhancement ratios were 1.29 +/- 0.15 (SD) with injection of SH L 643A and 1.61 +/- 0.31 with injection of gadopentetate dimeglumine (P <.01). In VX2 carcinomas, the enhancement ratios were not significantly different with injection of SH L 643A than with injection of gadopentetate dimeglumine at all time points. The mean difference between the enhancement ratios of the VX2 carcinomas and postoperative scars was 0.64 +/- 0.10 (range, 0.50-0.77) with SH L 643A and 0.36 +/- 0.16 (range, 0.17-0.66) with gadopentetate dimeglumine (P <.01). The mean microvessel density (in terms of vessels per field of view) was 10.7 +/- 5.5 for postoperative scars and 30.0 +/- 7.7 for VX2 carcinoma (P <.001). CONCLUSION: The difference between the enhancement ratios of postoperative scars and VX2 carcinomas with SH L 643A was greater than that with gadopentetate dimeglumine. Enhancement ratios at SH L 643A-enhanced MR imaging corresponded well with microvessel density in postoperative scars and VX2 carcinomas.     

Magnetic resonance imaging of myocardial perfusion and viability using a blood pool contrast agent

RATIONALE AND OBJECTIVES: A comprehensive cardiac magnetic resonance (MR) examination should comprise imaging of myocardial perfusion, viability, and the coronary arteries. Blood pool contrast agents (BPCAs) improve coronary MR angiography, whereas their potential for imaging of perfusion and viability is unknown. The abilities to noninvasively image myocardial perfusion and viability using the BPCA P792 (Guerbet, France) were tested in a closed-chest model of nonreperfused myocardial infarction in 5 pigs. MATERIALS AND METHODS: Two to 3 days after instrumentation, myocardial perfusion imaging with a saturation-recovery steady-state free precession technique and viability imaging with an inversion-recovery fast low-angle shot sequence were conducted on a 1.5-T MR scanner using the extracellular contrast agents (ECCA) Gd-DOTA (0.1 mmol Gd/kg) and blood pool contrast agent (BPCA) P792 (0.013 mmol Gd/kg). RESULTS: Perfusion defects were visualized in all pigs with good correlation between the ECCA and the BPCA (1.77 +/- 1.16 cm2 vs. 1.80 +/- 1.19 cm2, r = 0.959, P < 0.01). Reduced myocardial perfusion was detected using the ECCA up to 80 seconds after injection. In contrast, BPCA administration enabled visualization of perfusion defects on equilibrium perfusion imaging in all cases for 10 minutes. The size of myocardial infarction detected with viability MR imaging correlated well between the standard method (ECCA) and delayed-enhancement imaging with the BPCA (5.40 +/- 3.16 versus 5.52 +/- 3.13 cm3, r = 0.994, P < 0.002). CONCLUSIONS: The BPCA investigated in this study allows both reliable detection of perfusion defects on first pass and equilibrium perfusion imaging and characterization of viability after myocardial infarction. Thus, this contrast agent is suitable for a comprehensive cardiac MR examination.     

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.