Selective modification of NMR relaxation time in human colorectal carcinoma by using gadolinium-diethylenetriaminepentaacetic acid conjugated with monoclonal antibody 19-9.

Abstract

Monoclonal antibody 19-9 (mAb 19-9) against human colon adenocarcinoma was conjugated with gadolinium-diethylenetriaminepentaacetic acid (Gd-DTPA) and used as a contrast agent in nuclear magnetic resonance (NMR) in an effort to improve tumor target selectivity in nude mice. The data indicate that Gd-DTPA-mAb 19-9 in solution decreased the T1 relaxation of water protons at 90 MHz in direct proportion to the gadolinium concentration, and this effect was greater than in Gd-DTPA solutions. T1 relaxation time at 90 MHz, measured in tumors removed from nude mice 24 hr after injection of GdDTPA-mAb 19-9 (Gd, 20 pumol/kg; 16 DTPA molecules per mAb molecule), was significantly decreased (by 15%) as compared with the control group. Similar results were obtained in tumors from mice injected with GdDTPA-mAb 19-9 solutions in which Gd was used at 2, 6, or 10 jsmol/kg (16 DTPA molecules per mAb molecule). These doses are lower than those commonly used for GdDTPA (10-100 j#mol/kg) as contrast agent. Tumor localiztion by the Gd-DTPA-mAb 19-9 complex containing radioactive Gd (0.3 IACi/tg of ls3Gd) to confirm scintigraphy revealed significant concentrations of the complex (5% of the injected dose per gram of tissue) in the tumor. Scan images recorded in planar scintigraphy at day 5 showed good visualization of tumors.Nuclear magnetic resonance (NMR) proton imaging provides sharp contrast between tissues based on their intrinsic T1 and T2 relaxation times when varied pulse sequences are used. By exploiting the differences in relaxation times, images have been produced that provide previously unobtainable anatomic and physiologic information. Early investigators felt that differences in relaxation times between tumors and normal tissue made contrast agents unnecessary. However, despite this intrinsic tissue contrast, the absence of oral or intravenous contrast agents has proved disadvantageous (1, 2). Various intravenous and oral contrast agents have been proposed, including paramagnetic metal ions and their chelates and complexes (3, 4). Recently, attention has focused on gadolinium-diethylenetriaminepentaacetic acid (Gd-DTPA), a complex that produces a marked reduction in the proton relaxation ratio in vitro and in vivo and appears to have minimal acute toxicity in imaging doses (5, 6). One approach to increasing the specificity of NMR image contrast is to use paramagnetic contrast agents coupled with a monoclonal

Gd-25 DTPA-MAb, a potential NMR contrast agent for MRI in the xenografted nude mouse: Preliminary studies

“…In fact, as reported elsewhere (Solomon, 1984), gadolinium binding to this macromolecule causes an increase in the correlation time ( T~) of this paramagnetic complex, thus leading to an increase in the rate of relaxation. We had already noted this effect (Curtet, 1986) in comparing the T1 relaxation times of aqueous solutions with the same gadolinium concentrations in Gd-DTPA and Gd-DTPA-MAb 19-9 solutions.…”

“…In an earlier work (Curtet, 1986), we noted a specific and significant 15% modification in TI relaxation time (Gd 10 pmole/kg) with Gd15 DTPA-MAb complex. With 25 DTPA/MAb in the present study (Table II), this modification improved to 21.2% for MAb 19-9 and to 19.6% for MAb GA 73-3 with respect to tumour SW948 (Gd 17 pmole/ kg).…”

Monoclonal antibody conjugated to gadolinium as a contrast agent for magnetic resonance imaging of human rectal carcinoma

“…GdCl 3 in 10-fold excess of the Mab A7-EDTA conjugate was dissolved in 0.15 M sodium chloride and added to the Mab A7-EDTA conjugate. After stirring for 1 hr at 48C, gel filtration through Sephadex G-25 desalting column was performed in order to remove the excess GdCl 3 [7].…”

Concentration of Gadolinium-Diethylene Triamine Pentaacetic Acid in Human Kidney. Study on Proper Time for Dynamic Magnetic Resonance Imaging of the Human Kidney on Low and High Magnetic Fields.

“…Moreover, contrast media for MRI have been developed, although Gd-DTPA is the only clinically available contrast medium for MRI at present. Application of both FAST scan and Gd-DTPA has made dynamic MRI of several organs and tissues possible, especially in brain (Felix et al 1985), liver (Ohtomo et al 1987), kidney (Fuchs 1989;Ikehira et al 1985a, b), spleen (Mirowitz et al 1991), and colorectal cancer (Curtet et al 1986). However, the contrast enhancement effect of Gd-DTPA varies according to the pulse sequences used, and Gd-DTPA concentration (Gadian et al 1985).…”