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MR Probes BIOE 477/598 DP 04/18/2019

MR Probes BIOE 477/598 DP 04/18/2019. Molecular Imaging Modalities. Nuclear medicine - PET - SPECT MRI US Optical (NIRF) CT PAT Dual photon Optical coherence Bioluminescence. PET Cyclotron, Nuclear. Ultra Sound. CT/ SPECT-CT. Optical IVIS (Fluorescence, Luminescence).

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MR Probes BIOE 477/598 DP 04/18/2019

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  1. MR ProbesBIOE 477/598 DP04/18/2019

  2. Molecular Imaging Modalities • Nuclear medicine • - PET • - SPECT • MRI • US • Optical (NIRF) • CT • PAT • Dual photon • Optical coherence • Bioluminescence PET Cyclotron, Nuclear Ultra Sound CT/ SPECT-CT Optical IVIS (Fluorescence, Luminescence) Tools that enable visualization and quantification in space and over time of signals from molecular imaging agents MRI

  3. Characteristics of some Clinically Relevant Imaging Modalities Low sensitivity Short-lived radioisotopes Ca interference Slow Poor depth penetration www.scielo.br/.../bjp/v36n1a/a05tab01.gif

  4. NMR  MRI: Why the name change? most likely explanation: nuclear has bad implications History of MRI • NMR = nuclear magnetic resonance • nuclear: properties of nuclei of atoms • magnetic: magnetic field required • resonance: magnetic field x radio frequency • 1946: Bloch and Purcell • atomic nuclei absorb and re-emit radio • frequency energy • 1992: Ogawa and colleagues • first functional images using BOLD signal Bloch Purcell Ogawa

  5. Hydrogen nuclei have a quantum physics property called “spin”. In quantum physics terms, "spin" doesn't mean going round and round. MRI first “irritates” the hydrogen nuclei and then from their "responses", detects their presence. 

  6. The magnetic fields produced by the magnet is represented by the green lines with arrows. This magnetic field is continuously present and in our example, goes from the top to the bottom (direction of arrows). The magnetic field does something interesting to the spins of the hydrogen nuclei. The magnetic field (green lines) are going from the top to the bottom. The strong magnetic field makes the spins (blue arrows) of the hydrogen nuclei line up along the magnetic field. Some of the hydrogen nuclei line up in the direction of the magnetic field (lower nuclei in diagram) and other hydrogen nuclei line up opposite to the direction of the magnetic field (upper nuclei in diagram)

  7. There are also some hydrogen nuclei that have spins that are in the opposite direction to the magnetic field and have an "higher" energy. Labeled - "high energy nuclei" as "High" . After the magnetic field has made the nuclear spins line up, there are slightly more low energy nuclei than high energy nuclei.  It is the behavior of these low energy hydrogen nuclei that make MRI possible.

  8. The MRI machine applies a current to this energy producing coil for a short period. During this period, the coil produces energy in the form of a rapidly changing magnetic field (pink waves). The frequency (i.e. how often it changes in one second) of this changing field falls within the frequency range commonly used in radio broadcasts. Therefore this energy is often called "radio frequency" energy (RF energy) and the coil is often called an radio frequency coil ( RF coil).

  9. The hydrogen nuclei with low energy absorb the energy sent from the RF coil. The absorption of RF energy changes the energy state of the low energy hydrogen nuclei. Once the low energy nuclei absorb the energy, they change their spin direction and become high energy nuclei.

  10. After a short period, the RF energy is stopped. The hydrogen nuclei that recently became 'high energy' prefer to go back to their previous, 'low energy' state and they start releasing the energy that was given to them. They release the energy in the form of waves, which in the diagram below, is shown in red. The MRI machine has "receiver coils " (blue coil shown below) that receive the energy waves sent out by the nuclei. Having given up their energy, the nuclei change their spin direction and return to the low energy state that they were in before.

  11. The receiver coil converts the energy waves into an electrical current signal. In this way, the MRI machine is able to detect hydrogen nuclei in the body.

  12. Basic Physics of MRI • Nuclei line up with magnetic moments either in a parallel or anti-parallel configuration. • In body tissues more line up in parallel creating a small additional magnetization M in the direction of B0. Nuclear magnetic moments precess about B0. Nuclei spin axis not parallel to B0 field direction.

  13. Basic Physics of MRI NMRable Nuclei • Body 1H content is high due to water (>67%) • Hydrogen protons in mobile water are primary source of signals in fMRI and aMRI

  14. MRI-at a glance • Magnetic nuclei are abundant in the human body (H, C, Na, P, K) • Since most of the body is H2O, the Hydrogen nucleus is especially prevalent • Patient is placed in a static magnetic field • Magnetized protons (H nuclei) in the patient align in this field • Radio frequency (RF) pulses create oscillating magnetic field perpendicular to static field • Magnetic nuclei absorb the RF energy and enter an excited state • When the magnet is turned off, excited nuclei return to normal state & give off RF energy • Different elements absorb & give off different amounts of RF energy (different resonances) • The RF energy given off is picked up by the receiver coil & transformed into images • MRI offers the greatest “contrast” in tissue imaging technology • cost: about $1250 - $1600 • time: 30 minutes - 2 hours, depending on the type of study being done Closed (traditional) MRI Open MRI

  15. So what are we measuring in MR? • Relaxivity! • What is a relaxivity? Several processes by which nuclear magnetization prepared in a non-equilibrium state return to the equilibrium distribution. (how fast spins "forget" the direction in which they are oriented. The rates of this spin relaxation can be measured in both spectroscopy and imaging applications- T1 and T2)

  16. What is T1 and T2? • T1-Relaxation: Recovery • Recovery of longitudinal orientation of M along z-axis. • ‘T1 time’ refers to time interval for 63% recovery of longitudinal magnetization. • Spin-Lattice interactions. • T2-Relaxation: Dephasing • Loss of transverse magnetization Mxy. • ‘T2 time’ refers to time interval for 37% loss of original transverse magnetization. • Spin-spin interactions, and more.

  17. Basic Physics of MRI: T1 and T2 T1 is shorter in fat (large molecules) and longer in CSF (small molecules). T1 contrast is higher for lower TRs. T2 is shorter in fat and longer in CSF. Signal contrast increased with TE. • TR determines T1 contrast • TE determines T2 contrast.

  18. Rule of Thumb! • T1 relaxivity Bright signal • T2 relaxivity Dark signal

  19. MR Manipulation of Inherent Tissue Contrast Importance of Exogenous Contrast T1-weighted T2-weighted MRI has high contrast for different tissue types! Post-Gd T1 T1 Contrast TE = 14 ms TR = 400 ms T2 Contrast TE = 100 ms TR = 1500 ms Proton Density TE = 14 ms TR = 1500 ms Tissue T1 (ms) T2 (ms) Native Tissue Contrast Can Be Altered Pharmacologically Grey Matter (GM) 950 100 White Matter (WM) 600 80 Muscle 900 50 Cerebrospinal Fluid 4500 2200 Fat 250 60 Blood 1200 100-200

  20. Comparison with X-ray Contrast • In radiography (barium enema, UGI series, angiography, arthrography, etc.) we image the contrast agent itself. • In MR we usually do not image the contrast agent itself, but we image the water near the contrast agent that is affected by the contrast agent. • Contrast agents change the T1 of the water around them.

  21. Importance of chelates • Chelate means “claw” • Chelates surround an ion an make a cage around it • A chelate of gadolinium occupies all available space around the ion except one • Water molecules exchange in and out of that one spot. When in that spot, the spins have an extremely short T1. This accelerates the overall relaxation rate, shortening T1. M

  22. Equipments Needed 3T magnet RF Coil gradient coil (inside) Magnet Gradient Coil RF Coil Source: Joe Gati, photos

  23. The Magnet • Main field = B0 • Continuously on • Very strong : • Earth’s magnetic field = 0.5 Gauss / 1 Tesla (T) = 10,000 Gauss • 3 Tesla = 3 x 10,000  0.5 = 60,000 x Earth’s magnetic field http://strangeworldofmystery.blogspot.com/2008/12/does-earths-magnetic-field-leaking.html

  24. Safety Things fly! Anyone entering the magnet must be metal free

  25. Advantages • Excellent anatomical detail especially of soft tissues. • Visualizes blood vessels without contrast: magnetic resonance angiography (MRA). • Intravenous contrast utilized much less frequently than CT. Disadvantages • High operating costs. • Poor images of lung fields. • Inability to show calcification with accuracy. • Slow

  26. MOLECULAR IMAGING WITH MRI Molecular specific probes ESSENTIAL PROPERTIES SENSITIVITY SPECIFICITY BIO DISTRIBUTION (Pharmacokinetics) BIO COMPATIBILITY In vivo detection: 1 nM – 1 pM Molecular Contrast - = Background Foreground 8/33

  27. NON SPECIFIC CONTRAST AGENTS SPECIFIC CONTRAST AGENTS Ligand Blood circulation (MRA) Perfusion Receptor (Target) Reporter Vector • Cellreceptor • Gene sequence • Enzyme MOLECULAR IMAGING WITH MRI Exogeneous contrast agents MR contrast agent

  28. vector FexOy vector MOLECULAR IMAGING WITH MRI Increasing sensitivity by increasing the number of reporter molecules contrastagent Liposomes / Micelles Magnetic nanoparticles Lecithine/cholesterol Perfluoro- Octylbromide phospholipid Gd-DTPA lipid Gd-DTPA-PE Biotinylated DPPE phospholipide avidin (Ultra-)Small-Particle Iron-Oxide SPIO, USPIO PEG Size: 30 nm - 300 nm r1 ≈ 25 s-1.mM-1 Antibody antibody

  29. Loss of specificity Disturbance of the de pharmacokinetics MOLECULAR IMAGING WITH MRI Dilemma for molecular imaging with 1H paramagnetic contrast agents SENSITIVITY ENHANCEMENT WITH BIGGER CONTRAST AGENTS

  30. t Gd3+ Gd3+ Gd3+ Gd3+ Gd3+ Gd3+ Gd3+ HYDRATION SPHERE Gd3+ Gd3+ MOLECULAR IMAGING WITH MRI The sensitivity problem: molecular specific probes 9/33

  31. T1 Contrast Agents

  32. Paramagnetic Contrast Agents: Commercial MRI Agents • The first agent to be developed, gadopentetatedimeglumine (Magnevist): Linear structure & ionic • Followed in Europe by gadoteratemeglumine (Dotarem): Cyclic structure & ionic • Similar clinical effectiveness; Less transmetallation with the macrocyclics Gd-BOPTA Gadobenatedimeglumine is partially taken-up by hepatocytes and excreted via the bile (up to 5% of dose). The elimination half-life of gadobenatedimeglumine is ~ 1 hour. It is not metabolized. The gadobenate ion is excreted predominantly by the kidney; 78% to 96% recovered in the urine. Small molecule Positive Contrast Small molecule MR contrast agents

  33. Coupling to macromolecules/NP increases relaxivity by slowing the rotation of chelate Science 7 August 2009: Vol. 325. no.5941, pp. 701 - 704 MS-325 noncovalently couples to albumin increasing relaxivity from 5 to 50 L (mm*s)-1 Importance of macromolecules

  34. Gadomer-17: A Dendritic Contrast Agent Gadofluorine Micellar Blood Pool Contrast Agent Dendritic Pre Contrast Gadomer-17 is a dendritic gadolinium (Gd) chelate carrying 24 Gd ions (G3) After i.v. injection Gadomer-17 distributes almost exclusively within the intravascular space without significant diffusion into the interstitial space. After single i.v. injection in rats, the dendritic contrast medium was rapidly and completely eliminated from the body via glomerular filtration. Post Contrast IR turbo FLASH images before and 48 hours after application of Gadofluorine in 18-month-old WHHL rabbit at identical slice positions Misselwitz et al Magnetic Resonance Materials in Physics, Biology and Medicine Volume 12, Numbers 2-3 / June, 2001 Barkhausen et al Circulation. 2003;108:605. Micelles

  35. Gadolinium-based Agents MR T1-weighted images of mice with hepatocellular carcinoma before (A, C) and after injection of Gd(DOTA-RGD), (B) and c-(RGDyK)(D) 30 minutes prior the injection of Gd(DOTA-RGD). The color indicates the signal intensity according to the pseudo color scale on the right. 

  36. Contrast enhanced axial MR images and T1-maps of mice bearing human breast cancer cell line (MDA-MB-231) xenografts before and after injection of HPMA copolymer-(Gd-DOTA) conjugate (A), HPMA copolymer-(Gd-DOTA)-RGDfK conjugate (B), and HPMA copolymer-(DOTA)-RGDfK conjugate followed by injection of HPMA copolymer-(Gd-DOTA)-RGDfK conjugate after 2 h (C). Comparison of T1 values at tumor sites at different time points (D). The polymers were injected intravenously at a dose of 0.03mmol-Gd/kg. The arrows point to the tumor. The color scales are reflective of T1-values. The arrival of the contrast reduces the T1-value of the tumor as seen by the color differences and begins to normalize back to its original value after about 6 h.

  37. Synthetic scheme of biodegradable c(RGDfK) targeted poly(L-glutamic acid)-cystamine-(Gd-DO3A) conjugate (A). T1-maps of mice bearing human prostate carcinoma DU145 (left flank) and Kaposi's sarcoma SLK (right flank) xenografts before and after injection of the c(RGDfK) containing PGA-cystamine-(Gd-DO3A) conjugate (B) and PGA-cystamine-(Gd-DO3A) (C).

  38. T2 Contrast Agents

  39. Superparamagnetic Iron Oxides A wide variety of iron oxide based nanoparticles have been developed that differ in hydrodynamic particle size and surface coating material (dextran, starch, albumin, silicones) In general terms, these particles are categorized based upon nominal diameter into superparamagnetic iron oxides (SPIO, 50nm to 500nm) and ultra-small superparamagnetic iron oxides (USPIO, < 50 nm). Size dictates their physicochemical and pharmacokinetic properties. Negative Contrast

  40. USPIOs as a Marker of Atherosclerosis-Associated Inflammatory Changes in the Vessel Wall before Luminal Narrowing is Present A, Coronal MIP and (B) sagittal oblique and (C) coronal oblique reformatted images of contrast-enhanced 3D MRA data set collected after intravenous administration of Gd-DOTA displaying aorta of 7-month-old hyperlipidemic rabbit. Aortic wall is smooth, without evidence of luminal narrowing. Circulation.201; 103: 415-422

  41. What Happens After the Administration of USPIOs A, Coronal MIP and (B) sagittal oblique and (C) coronal oblique reformatted images of contrast-enhanced 3D MRA data sets of same hyperlipidemic rabbit as depicted in Figure 1 obtained 5 days after intravenous injection of USPIO agent Sinerem. Note susceptibility effects originating within vessel wall and representing Fe uptake in macrophages embedded in plaque.

  42. The Curious Case of Sinerem Sinerem/ferumoxtran-10: Developed and sold by Advanced Magnetics (and later known as AMAG Pharma), Ferumoxtran-10 was an imaging agent that, when used in combination with magnetic resonance imaging (MRI), appeared to be able to make visible, with considerable accuracy, the presence of cancer-containing lymph nodes in patients with progressive prostate cancer. In Europe the brand name from feromoxtran-10 was Sinerem; in the USA it has long been known as Combidex. Combidex was approved in some European countries, however had never succeeded in gaining approval in the USA. In late 2003 a paper by Harisinghani et al. in the New England Journal of Medicine offered extraordinary images of the way in which ferumoxtran-10 could demonstrate the presence of positive lymph nodes in patients with prostate cancer. However, ODAC voted 15 to 4 not to recommend approval of the proposed indication for this drug in the USA, stating that there were insufficient clinical data to support a broad indication for use of ferumoxtran-10 to differentiate metastatic from non-metastatic lymph nodes across all cancer types. For many years there have been small numbers of patients who would travel to the Netherlands to get their lymph nodes checked using ferumoxtran-10. However, the maufacturer terminated production of the product several years ago.  http://prostatecancerinfolink.net/2010/03/24/the-demise-of-combidexsinerem/

  43. Of the 334 lymph nodes that underwent resection or biopsy, 63 (18.9 percent) from 33 patients (41 percent) had histopathologically detected metastases. Of these 63 nodes, 45 (71.4 percent) did not fulfill the usual imaging criteria for malignancy. MRI with lymphotropicsuperparamagnetic nanoparticles correctly identified all patients with nodal metastases, and a node-by-node analysis had a significantly higher sensitivity than conventional MRI (90.5 percent vs. 35.4 percent, P<0.001) or nomograms.

  44. N Engl J Med 2003; 348:2491-2499

  45. Schematic illustration of coupling c(RGDyK) peptide to Fe3O4 nanoparticles (upper). Axial T2-weighted MR images of the U87MG tumors implanted in mice without nanoparticles (A), with injection of 300 μg of c(RGDyK)-MC-Fe3O4nanoparticles (B) and with the injection of c(RGDyK)-MC-Fe3O4 nanoparticles free c(RGDyK) (C). Prussian blue staining of U87MG tumors for c(RGDyK)-MC-Fe3O4 nanoparticles (D), both (RGDyK)-MC-Fe3O4 nanoparticles and free c(RGDyK) (E). High resolution TEM image of 4.5 nm MC-Fe3O4 nanoparticles (F).

  46. Atherosclerotic Plaque and Angiogenesis • Plaque deposits- consisting of fats, cholesterol and other materials • Gradually accumulate in the lining of the arteries (Thickening and loss of elasticity of arterial walls/ Hardening of the arteries) • The plaques will fracture at an edge, forming a mobile flap of plaque debris that may break off and lead to stroke. http://www.gehealthcare.com/ Seeing and quantifying atherosclerotic angiogenesis in cholesterol-fed rabbit with avb3-Mn nanocolloids • Linking of angiogenesis with atherosclerotic plaque • A possible marker for vulnerable plaque In vivo T1 sagittal section spin-echo image to display long axis of aorta from aortic arch to diaphragm of cholesterol-fed rabbit • Sensitivity of detection • Target specificity Kd < 10 nM • High affinity ligand for integrinavb3 Pan D. et al. Circulation 2010, 122, A20216

  47. NSF and Why Gd Should be Avoided NSF lawsuit advertisement Issues Toxicity: Recent discovery of NSF associated with Gd based MRI agents BOXED WARNING: NEPHROGENIC SYSTEMIC FIBROSIS (NSF) Gadolinium-based contrast agents increase the risk for nephrogenic systemic fibrosis (NSF) in patients with: • Acute or chronic severe renal insufficiency (glomerular filtration rate <30mL/min/1.73m2) or • Acute renal insufficiency of any severity due to the hepato-renal syndrome or in the perioperative liver transplantation period. Patient with NSF

  48. MRI Agents Based on Non-lanthanides Lanthanide gadolinium is NOT safe: Linked to Nephrogenic Systemic Fibrosis (NSF) • Promise • Fe(III), Mn(II), Mn(III), Cu(II) • Favorable biochemistry • Limitation • Sensitivity • Lack of suitable nano platforms • Safety • Solution • Nano-engineering approach • Safe • Efficient • Commercially amenable Metals in the form of organometallics /organically soluble complexes and NP No metals on the surface as contrary to commonly pursued approaches, 80-200nm • Pre-requisites:Bio-metabolizablenanoparticle with at least 100,000 metal/NP with specificity in the nanomolar range. Pan et. al. J Am Chem Soc. 2008 Jul 23;130(29):9186-7. Pan et. al. Chem Commun (Camb). 2009, 22, 3234-6.

  49. USPIO Assessment of Atherosclerotic Plaques SPIO are Useful For Identifying Hepatic Tumors Before Targeting After Targeting Pre Contrast Post Contrast Tanimoto et al Organ Microcirculation, 2005 Left: Axial T2-weighted sequence of the liver with high signal metastasis Right: Signal dropout in the normal liver following infusion of Endorem, (Guerbert, UK), with increased definition of the metastasis Trivedi et al Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:1601. Cardiovascular MR Imaging Long waiting time before scanning 24-48h

  50. β-galactosidase Enzym-mediated contrast agent CLIO Ca2+mediatedcontrast agent Gen-sequencespecific contras tagent (also for Zn2+ en pH) MOLECULAR IMAGING WITH MRI ‘Smart’ contrast agents H2O T « Switch-on / switch-off » probes Liposome membrane Temperature sensitive contrast agent 11/33

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