Physicochemical and Biological Evaluation of P792, a Rapid-Clearance Blood-Pool Agent for Magnetic Resonance Imaging

Port, Marc; Corot, Claire; Raynal, Isabelle; Idée, Jean‐Marc; Dencausse, Anne; Lancelot, Eric; Meyer, Dominique; Bonnemain, Bruno; Lautrou, Jean

doi:10.1097/00004424-200108000-00002

Cited by 73 publications

(65 citation statements)

References 41 publications

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“…The time interval between the injections of the contrast agents in the current study was thus chosen to be about five times the blood half-life of Gd-DOTA and P792. The absence of significant hemodynamic effect of the intravenous injection of Gd-DOTA, P792, and P717 has been reported previously (23).…”

Section: Mrimentioning

confidence: 55%

“…Gd-DOTA (gadoterate, Dotarem, Guerbet, Roissy, France) is a commercially available gadolinium chelate, P792 (gadomelitol, Vistarem, Guerbet, Roissy, France) is a higher-molecular-weight blood pool agent, and P717 is a high-molecular-weight carboxymethyldextran-Gd-DOTA (23). According to the differences in molecular weight and size, differences in plasma clearance and distribution volume are observed between the three contrast agents (23). The contrast agents remain extracellular and are excreted by renal glomerular filtration.…”

Section: Mrimentioning

confidence: 99%

“…The reported blood elimination half-life of Gd-DOTA in rats is 18 minutes (24). P792 has a similar short elimination half-life, despite its limited diffusion across the normal endothelium (23). The time interval between the injections of the contrast agents in the current study was thus chosen to be about five times the blood half-life of Gd-DOTA and P792.…”

Section: Mrimentioning

confidence: 99%

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Transvascular and interstitial transport in rat hepatocellular carcinomas: Dynamic contrast‐enhanced MRI assessment with low‐ and high‐molecular weight agents

Michoux

Huwart

Abarca‐Quinones

et al. 2008

Magnetic Resonance Imaging

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Purpose:To assess which MRI-derived kinetic parameters reflect decreased transvascular and interstitial transport when low-and high-molecular-weight agents are used in rat hepatocellular carcinomas. Materials and Methods:Dynamic MRI after injection of a low-molecular-weight contrast agent of 0.56 kDa (Gd-DOTA, gadoterate) and two high-molecular-weight contrast agents of 6.47 kDa (P792, gadomelitol) and 52 kDa (P717, carboxymethyldextran Gd-DOTA) was performed in rats with chemically induced hepatocellular carcinomas. The data were analyzed with the Kety compartmental model, the extended Kety compartmental model in which it is assumed that the tissue voxels contain a vascular component, and the St Lawrence and Lee distributed-parameter model. Results:The extravascular extracellular space accessible to the contrast agent v e and the extraction fraction E decreased with increasing molecular weight of the contrast agent. In contrast, the volume transfer constant Ktrans did not differ significantly when low-or high-molecular-weight agents were used. Conclusion:In this animal model the results suggest that the accessible extravascular extracellular space and the extraction fraction are more sensitive indicators of decreased transvascular and interstitial transport with highmolecular-weight agents than the volume transfer constant, which is a lumped representation of blood flow and permeability.

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Section: Mrimentioning

confidence: 55%

Section: Mrimentioning

confidence: 99%

Section: Mrimentioning

confidence: 99%

See 1 more Smart Citation

Transvascular and interstitial transport in rat hepatocellular carcinomas: Dynamic contrast‐enhanced MRI assessment with low‐ and high‐molecular weight agents

Michoux

Huwart

Abarca‐Quinones

et al. 2008

Magnetic Resonance Imaging

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“…The molecular weight of the compound is 6.47 kDa, but the mean diameter of P792 is 50.5 Å and the T1 relaxivity of this agent is 29 mM À1 s À1 at 60 MHz (Port et al, 2001a). The apparent hydrodynamic volume of P792 is 125 times greater than that of Gd-DOTA (gadoterate meglumine, Dotarem) and as a result of this high molecular volume, P792 is characterised by a limited diffusion across the normal endothelium and therefore ideally suited to study hyperpermeable neoplastic vessels (Port et al, 2001b).…”

Section: Magnetic Resonance Imagingmentioning

confidence: 99%

Recombinant human erythropoietin α modulates the effects of radiotherapy on colorectal cancer microvessels

et al. 2007

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Recent data suggest that recombinant human erythropoietin (rhEPO) modulates tumour growth and therapy response. The purpose of the present study was to examine the modulation of radiotherapy (RT) effects on tumour microvessels by rhEPO in a rat colorectal cancer model. Before and after 5 Â 5 Gy of RT, dynamic contrast-enhanced -magnetic resonance imaging was performed and endothelial permeability surface product (PS), plasma flow (F), and blood volume (V) were modelled. Imaging was combined with pO 2 measurements, analysis of microvessel density, microvessel diameter, microvessel fractal dimension, and expression of vascular endothelial growth factor (VEGF), hypoxia-inducible factor-1 a (HIF-1a), Bax, and Bcl-2. We found that RT significantly reduced PS and V in control rats, but not in rhEPO-treated rats, whereas F was unaffected by RT. Oxygenation was significantly better in rhEPOtreated animals, and RT induced a heterogeneous reoxygenation in both groups. Microvessel diameter was significantly larger in rhEPO animals, whereas VEGF expression was significantly lower in the rhEPO group. No differences were observed in HIF-1a, Bax, or Bcl-2 expression. We conclude that rhEPO results in spatially heterogeneous modulation of RT effects on tumour microvessels. Direct effects of rhEPO on neoplastic endothelium are likely to explain these findings in addition to indirect effects induced by increased oxygenation. British Journal of Cancer (2007) Anaemia commonly occurs in colorectal cancer patients especially if they are treated with neoadjuvant radiotherapy (RT) or chemotherapy. Anaemia not only adversely affects the clinical condition of these patients, but also contributes to the development of tumour hypoxia, recognised as a major negative determinant of sensitivity to RT, chemoradiotherapy, and certain chemotherapeutic agents (Harrison and Blackwell, 2004;van Halteren et al, 2004).Recent clinical studies have shown that administration of recombinant human erythropoietin (rhEPO, epoetin alfa) increases haemoglobin levels and improves quality of life in patients with cancer-related anaemia (Littlewood et al, 2001). Over the last decade, it has become clear that the action or rhEPO extends into a wide range of cellular mechanisms involved in stem cell development, maintenance of cellular integrity, and physiological angiogenesis (Maiese et al, 2005). The demonstration of the erythropoietin (EPO) receptor in various neoplastic tissues and the observation in a recent clinical trial that mortality was higher in nonanaemic rhEPO-treated breast cancer patients highlighted the possible effects of rhEPO on tumour growth and angiogenesis (Leyland-Jones, 2003). Preclinical studies investigating the role of EPO and EPO -EPO receptor signalling on tumour growth and angiogenesis have yielded contradictory results. Yasuda et al (2003) noted the inhibition of angiogenesis and tumour cell survival in stomach and melanoma xenografts following blockade of EPO signalling. The results of Hardee et al (2005), however, suggested that a...

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“…P792 is a monodisperse, monogadolinated macrocyclic gadolinium complex based on a Gd-DOTA core and has been designed for human use (8,14). Four hydrophilic arms account for the intravascular properties, whereas the molecular weight of 6.47 kDa allows for renal elimination.…”

Section: Blood Pool Contrast Agentmentioning

confidence: 99%

Three‐dimensional navigator coronary MRA with the aid of a blood pool agent in pigs: Improved image quality with inclusion of the contrast agent first‐pass

Dirksen

Kaandorp

Lamb

et al. 2003

Magnetic Resonance Imaging

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Purpose:To evaluate the effect of including the first-pass of a blood pool agent (BPA) on the image quality of threedimensional navigator coronary MRA. Materials and Methods:A pig model was used to perform: 1) T1 simulation of the BPA, based on actual blood samples, and 2) BPA-enhanced three-dimensional navigator coronary MRA, with or without inclusion of the first-pass of the BPA. The acquisitions with inclusion of the first-pass were timed with the use of a test bolus. The acquisitions without firstpass were started one minute after bolus injection (steadystate). A gradient echo acquisition technique with centric kspace sampling was applied. Comparison of both acquisitions was based on determination of contrast-to-noise ratio (CNR), signal-to-noise ratio (SNR), and vessel length.Results: T1 simulation shows a distinct T1 reduction during first-pass (to a level below 50 msec), increasing to 190 msec during steady-state. Images obtained with first-pass inclusion showed improved CNR (8.6 Ϯ 1.7 vs. 4.5 Ϯ 1.8), SNR (11.9 Ϯ 1.6 vs. 7.4 Ϯ 2.0), and vessel length (99.2 Ϯ 10.9 mm vs. 60.5 Ϯ 21.8 mm) as compared to the acquisitions during steady-state only (all: PϽ 0.05). Conclusion:The image quality of three-dimensional navigator coronary MRA combined with a gadolinium BPA in pigs is improved when starting the image acquisition during first-pass of the bolus. VARIOUS TYPES OF CONTRAST MEDIA are being explored for optimization of coronary magnetic resonance angiography (MRA) (1-5). Contrast agents have been developed that selectively remain in the circulation without extravasation to the interstitial space (6 -9). These so-called blood pool agents (BPA) can improve the contrast of coronary MRA images (2,3,10,11). Due to their slow elimination, BPAs maintain high plasma levels, allowing for prolonged acquisition times, such as coronary MRA combined with real-time navigator gating.It is well known that the first-pass effects of conventional contrast media can improve the image quality of breath-hold acquisitions, especially when central k-lines are obtained in the early phase of data acquisition (4,5,12,). The value added by using first-pass effects has not been the subject of research for acquisitions that require several minutes of acquisition time, such as navigator coronary MRA. During first-pass, T1 reduction may be more pronounced and may dominate the contrast behavior when the central k-lines are obtained during this short time period. This may be of value not only for breath-hold acquisitions of short duration, but may also be of value for navigator coronary MRA. This would allow further optimization of the clinical application of navigator coronary MRA.The purpose of the present study was to evaluate the image quality of three-dimensional navigator coronary MRA combined with a blood pool contrast agent, either with or without the inclusion of the first-pass. MATERIALS AND METHODS Study DesignThe T1 characteristics of a BPA (Vistarem, P792; Guerbet Research, Aulnay s. Bois, France) were evaluated during first-pass...

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Physicochemical and Biological Evaluation of P792, a Rapid-Clearance Blood-Pool Agent for Magnetic Resonance Imaging

Cited by 73 publications

References 41 publications

Transvascular and interstitial transport in rat hepatocellular carcinomas: Dynamic contrast‐enhanced MRI assessment with low‐ and high‐molecular weight agents

Transvascular and interstitial transport in rat hepatocellular carcinomas: Dynamic contrast‐enhanced MRI assessment with low‐ and high‐molecular weight agents

Recombinant human erythropoietin α modulates the effects of radiotherapy on colorectal cancer microvessels

Three‐dimensional navigator coronary MRA with the aid of a blood pool agent in pigs: Improved image quality with inclusion of the contrast agent first‐pass

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