Detailed Toxicity Studies of Liposomal Gadolinium-DTPA

Fritz, Thomas; Unger, Evan C.; Wilson-Sanders, Susan E; Ahkong, Quet F.; Tilcock, Colin

doi:10.1097/00004424-199111000-00007

Cited by 24 publications

(8 citation statements)

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“…The restricted access of the extracapsular water molecules to the contrast agents in the interior of the liposomes makes them less effective. Additional problems arise due to the comparatively long half-life of several days for the hepatic clearance of Gd-DTPA and the associated potential toxicity [256]. Finally, a typical MION-46 agent, with mean particle diameter of 18–24 nm and R 2 ∼ 7200 mM −1 s −1 is estimated to require a minimum concentration of 1.6 × 10 −5 niM for visibility in MRI.…”

Section: Magnetic Nanoparticle Applications In Biomedicinementioning

confidence: 99%

Biomedical Nanomagnetics: A Spin Through Possibilities in Imaging, Diagnostics, and Therapy

2010

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Biomedical nanomagnetics is a multidisciplinary area of research in science, engineering and medicine with broad applications in imaging, diagnostics and therapy. Recent developments offer exciting possibilities in personalized medicine provided a truly integrated approach, combining chemistry, materials science, physics, engineering, biology and medicine, is implemented. Emphasizing this perspective, here we address important issues for the rapid development of the field, i.e., magnetic behavior at the nanoscale with emphasis on the relaxation dynamics, synthesis and surface functionalization of nanoparticles and core-shell structures, biocompatibility and toxicity studies, biological constraints and opportunities, and in vivo and in vitro applications. Specifically, we discuss targeted drug delivery and triggered release, novel contrast agents for magnetic resonance imaging, cancer therapy using magnetic fluid hyperthermia, in vitro diagnostics and the emerging magnetic particle imaging technique, that is quantitative and sensitive enough to compete with established imaging methods. In addition, the physics of self-assembly, which is fundamental to both biology and the future development of nanoscience, is illustrated with magnetic nanoparticles. It is shown that various competing energies associated with self-assembly converge on the nanometer length scale and different assemblies can be tailored by varying particle size and size distribution. Throughout this paper, while we discuss our recent research in the broad context of the multidisciplinary literature, we hope to bridge the gap between related work in physics/chemistry/ engineering and biology/medicine and, at the same time, present the essential concepts in the individual disciplines. This approach is essential as biomedical nanomagnetics moves into the next phase of innovative translational research with emphasis on development of quantitative in vivo imaging, targeted and triggered drug release, and image guided therapy including validation of delivery and therapy response.

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Section: Magnetic Nanoparticle Applications In Biomedicinementioning

confidence: 99%

Biomedical Nanomagnetics: A Spin Through Possibilities in Imaging, Diagnostics, and Therapy

2010

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“…Free gadolinium ion is known to be toxic to cells. Release of gadolinium within the intracellular environment may be responsible for the toxic changes in the liver and spleen that we observed in our study of subacute toxicity of liposomal Gd-DTPA in mice (13).…”

Section: Resultsmentioning

confidence: 64%

Clearance of liposomal gadolinium: In vivo decomplexation

Unger

Fritz

Tilcock

et al. 1991

Magnetic Resonance Imaging

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The contrast agents gadolinium-DTPA (diethylenetriaminepentaacetic acid), Gd-DOTA (tetraazacyclododecanetetraacetic acid), and Gd-HP-DO3A (1,4,7-tris[carboxymethyl]-10-[2' hydroxypropyl]-1,4,7,10-tetraazacyclododecane) are used in humans as extracellular contrast agents. Although free Gd+ ion is toxic, the intact Gd3+ complexes are rapidly excreted and are relatively nontoxic. Decomplexation with release of free gadolinium is a relevant clinical concern in patients with altered renal clearance. Blood pool contrast agents currently under development may have longer clearance half-lives and be more prone to decomplexation. The present study was designed to evaluate the clearance of liposomally encapsulated Gd3+ complexes (DTPA, DOTA, and HP-DO3A). The macrocyclic compounds had more rapid and complete clearance than DTPA (P less than .05). Parallel studies with carbon-14 and Gd-153-labeled complexes showed significant differences (P less than .05) in the amount of these isotopes retained in the heart, kidney, lungs, and spleen, providing strong supportive evidence for in vivo decomplexation.

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“…The acute toxicity of free Gd-DTPA and liposomal Gd-DTPA was similar (8). Clearance from the liver occurred with a T l l 2 of about 3 f days ( 9 ) .…”

Section: Introductionmentioning

confidence: 90%

“…Subacute toxicity studies showed that liposomal Gd-DTPA at prolonged high doses (2,3 caused splenomegaly and damage to the bone marrow, liver, and spleen (8). Recently in parallel clearance studies using I4C and 153Gd labels of liposomally entrapped gadolinium complexes, we showed that there was decomplexation of liposomal gadolinium in vivo from DTPA and to a much lesser extent from DOTA (10).…”

Section: Introductionmentioning

confidence: 99%

Liposomes as MR contrast agents: Pros and cons

Unger

Shen

et al. 1991

Magnetic Resonance in Med

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Liposomes are generally thought of as being useful for entrapping drugs within their internal aqueous space. When used with MR contrast agents, this has the drawback that water flux across the membrane bilayer is limiting to contrast enhancement. This can be partially overcome by making the liposomes very small, such that surface area is relatively great compared to internal volume, thereby facilitating water exchange. Alternatively the membranes can be designed to be permeable to water but this may render the vesicles unstable in serum. Another approach is to incorporate the contrast agents into the lipid bilayer. By designing novel complexes of manganese with the ligands incorporated onto dual acyl chains, we have achieved R1 and R2 values of over 20/mmol sec-1 or more than five times higher than Gd-DTPA. Hepatic metastasis detection is significantly improved in rats at doses of only 10 mumol/kg manganese. Membrane-bound manganese complexes function as highly effective liver imaging agents and merit further study for development as agents to undergo human clinical trials.

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Detailed Toxicity Studies of Liposomal Gadolinium-DTPA

Cited by 24 publications

References 0 publications

Biomedical Nanomagnetics: A Spin Through Possibilities in Imaging, Diagnostics, and Therapy

Biomedical Nanomagnetics: A Spin Through Possibilities in Imaging, Diagnostics, and Therapy

Clearance of liposomal gadolinium: In vivo decomplexation

Liposomes as MR contrast agents: Pros and cons

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