Tumor specific MRI contrast agents are pharmaceuticals that are targeted to tumors, either specifically or nonspecifically. Monoclonal antibodies are targeted to specific tumors such as adenocarcinoma of the colon. Metalloporphyrins exhibit affinity for many tumor types including carcinoma, sarcoma, neuroblastoma, melanoma and lymphoma.
NOTE: This article has been transferred from mritutor.org and was last updated in March 5, 1996. Review and edit pending.
Monoclonal antibodies (McAb) are used successfully in nuclear medicine for localization of tumors but an initial attempt at extending this use to MRI with paramagnetic (Gd3+) labeled antibodies was unsuccessful because of the estimated 800-fold lesser sensitivity of MRI. This problem can be addressed in several ways: 1) increasing the number of paramagnetic ions attached to the McAb; 2) attaching several paramagnetic ions to a macromolecule that in turn is attached to a McAb; 3) using more antibodies or those with an affinity to many antigenic sites per cell or both; and 4) using a superparamagnetic particle attached to the McAb. Implanted human colon carcinoma tumors in mice have been successfully imaged by using monoclonal antibodies with a large number of Gd-DTPA molecules attached.
Additional studies report the use of very small magnetite particles coated with McAb. The magnetite cores are 10-20 nm in diameter with a total particle diameter of 20-32 nm. The magnetic moment of these superparamagnetic particles is about 1000 times that of comparable paramagnetic particles. This allows the use of 1-10 nmol concentrations of the McAb coated magnetite particles. Mixed success has been obtained in rodents with implanted neuroblastoma and human colon carcinoma.
The metalloporphyrin most commonly used as a MRI contrast agent is Mn(III)TPPS4 (manganese(III) tetra-[4- sulfanatophenyl] porphyrin) because of its low toxicity (compared to Fe(III)TPPS4 for example). A safety ratio of about 6:1 is estimated in mice. This material appears to work best with tumors that are isointense to surrounding structures on T1-weighted sequences. Incidentally, the fluorescent and tumor localizing characteristics of porphyrin derivatives have been exploited in phototherapy of tumors.
Nitroxide stable free radicals or nitroxyl spin labels as they may be called, are chemically stable organic compounds that have an unpaired electron that results in paramagnetic properties. They generally consist of a six- member ring piperidine derivative or a five-member ring pyrroxamide derivative. The pharmacokinetics of nitroxides are similar to iodinated contrast agents and Gd- DTPA. They do not cross an intact blood brain barrier and undergo glomerular filtration as a dominant route of elimination. Their ease of conjugation to various biomolecules makes them attractive for targeting to various organ systems. Nitroxides are chemically stable and show limited in vivo metabolism. Their relaxation effects in vivo can be eliminated almost immediately by IV injection of sodium ascorbate, a strong reducing agent. This will allow an unenhanced MR study to be performed immediately after a contrast enhanced study, if the contrast study is not satisfactory alone.
The early ionic derivatives of piperidine have a 38 minute half-life and a safety ratio of between 8:1 and 100:1. Nonionic pyrrolidine derivatives are formulated with a longer half-life of 45-50 minute in dogs, estimated to be about 2 hours in humans. The LD50 in mice of this nonionic formulation is about 25 mmol/kg, making it twice as safe as earlier ionic piperidinyl preparations. Mutation and toxicity studies show no evidence of genetic or other cellular damage in mammalian cell preparations.
Larger molecular weight nitroxides exhibit increased relaxation rates as do paramagnetic ions attached to macromolecules. This phenomenon occurs when attaching five-membered nitroxide rings to fatty acids. The fatty acids attach to human serum albumin, either in vitro or in vivo, resulting in a significant increase in relaxation rate. Safety studies and clinical trials need to be performed before nitroxides will be available for use.
Ferrioxamine methanesulfonate is a paramagnetic contrast agent that has undergone phase I and phase II clinical trials for use as an IV and retrograde contrast agent for the kidneys, ureters and bladder. It is more stable than Gd-DTPA, though its relaxivity is somewhat less, as expected from it having 5 unpaired electrons, vs 7 unpaired electrons for Gd-DTPA. 80% is eliminated by renal excretion and 20% by hepatic excretion. Ferrioxamine undergoes renal excretion by glomerular filtration but is actively reabsorbed in the tubules. This results in a longer plasma half-life than Gd-DTPA (128 min. vs 20 min. in rats).
In clinical imaging the long plasma half-life allows enhancement of the kidneys for 60 minutes with little change in intensity. Significant improvement in detectability of lesions in the kidneys is demonstrated over unenhanced controls. Side effects include epigastric distress and transient burning at the injection site. Increase in serum iron levels and a transient elevation of serum liver enzymes (SGOT/SGPT) have been reported.
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Physics and Imaging Technology: MRI
- MRI (introduction)
- chemical shift
- dependence of magnetization (proton density, field strength and temperature)
- echo time
- eddy currents
- electromagnetic induction
- Ernst angle
- flip angle
- Larmor frequency
- magnetic dipolemagnetic field gradient
- magnetic susceptibility
- molecular tumbling rate effects on T1 and T2
- net magnetization vector (NMV)
- repetition time
- resonance and radiofrequency (RF)
- units of magnetism
- MRI hardware
- signal processing
MRI pulse sequences (basics | abbreviations | parameters)
- CSF flow studies
- diffusion weighted sequences (DWI)
- echo-planar pulse sequences
- fat-suppressed imaging sequences
- gradient echo sequences
- inversion recovery sequences
- metal artifact reduction sequence (MARS)
- derived values
- saturation recovery sequences
- spin echo sequences
- spiral pulse sequences
- susceptibility-weighted imaging (SWI)
- T1 rho
- MR angiography (and venography)
MR spectroscopy (MRS)
- 2-hydroxyglutarate peak: resonates at 2.25 ppm
- alanine peak: resonates at 1.48 ppm
- choline peak: resonates at 3.2 ppm
- citrate peak: resonates at 2.6 ppm
- creatine peak: resonates at 3.0 ppm
- functional MRI (fMRI)
- gamma-aminobutyric acid (GABA) peak: resonates at 2.2-2.4 ppm
- glutamine-glutamate peak: resonates at 2.2-2.4 ppm
- Hunter's angle
- lactate peak: resonates at 1.3 ppm
- lipids peak: resonates at 1.3 ppm
- myoinositol peak: resonates at 3.5 ppm
- MR fingerprinting
- N-acetylaspartate (NAA) peak: resonates at 2.0 ppm
- MRI hardware and room shielding
- MRI software
- patient and physiologic motion
- tissue heterogeneity and foreign bodies
- Fourier transform and Nyquist sampling theorem
MRI contrast agents
- gadolinium contrast agents
- gastrointestinal MRI contrast agents
- reticuloendothelial MRI contrast agents
- tumor-specific MRI contrast agents
- intravascular (blood pool) MRI contrast agents
- hepatobiliary MRI contrast agents
- extracellular MRI contrast agents
- contrast media safety
- MRI safety