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Lecture 23 BIOE 498/598 DP 04/27/2014

Lecture 23 BIOE 498/598 DP 04/27/2014. Topics to Cover. Types of MR contrast agent- signal Types of MR contrast agents- specficity T1-weighted small molecule contrast agents T2-weighted contrast agents Actively targeted contrast agents

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Lecture 23 BIOE 498/598 DP 04/27/2014

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  1. Lecture 23BIOE 498/598 DP04/27/2014

  2. Topics to Cover • Types of MR contrast agent- signal • Types of MR contrast agents- specficity • T1-weighted small molecule contrast agents • T2-weighted contrast agents • Actively targeted contrast agents • Nephrogenic systemic fibrosis and issues of lanthanides • Non-lanthanide MR contrast agents • Increasing the sensitivity • Successful preclinical examples of targeted imaging • Examples of dual-modal imaging with MR • Other possible ways to increase senitivity • MRI with heteronuclear atoms • CEST • Hyperpolarization

  3. 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

  4. 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

  5. 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

  6. 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

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

  8. T1 Contrast Agents

  9. 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

  10. 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

  11. 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

  12. 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. 

  13. 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.

  14. 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).

  15. T2 Contrast Agents

  16. 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

  17. 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

  18. 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.

  19. Ex vivo imaging of contrast-filled aortic specimen of (A) hyperlipidemic rabbit 5 days after administration of Sinerem, (B) normal control rabbit 5 days after administration of Sinerem, and (C) hyperlipidemic rabbit that did not receive Sinerem. Marked susceptibility artifacts are present in aortic wall of hyperlipidemic rabbit that had received Sinerem (A). No such changes are visualized in other 2 rabbits (B, C). Cross-sectional histopathological sections with Prussian blue staining of aorta of same hyperlipidemic rabbit, killed 5 days after administration of USPIO agent Sinerem. Note thickening of intima with marked staining of Fe particles embedded in atherosclerotic plaque formations.

  20. 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/

  21. 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.

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

  23. 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).

  24. 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

  25. Imaging (1.5T) of Thrombus with PFC NP Cardiovascular imaging High Detection Sensitivity 0.7 x0.7mm High Contrast and Resolution 0.1 x0.1mm Canine External Jugular Vein Human CEA specimen (2h) Increasing Payload High Molecular Relaxivity Thrombus in vivo Unstable Plaque ex vivo Wickline et al J Magn Reson Imaging 2007; 25: 667-680 “HOT SPOT” MRI Lanza Wickline Circulation 2001; 104: 1280-1285.

  26. Molecular Imaging of avb3 in VX2 In Vivo 3D neovascular maps of example Vx-2 tumors on day 16 following treatment with avb3 -targeted fumagillin nanoparticles (top) vs. avb3 -nanoparticles without drug (bottom). Note the asymmetric distribution of angiogenic signal (blue) over the tumor surface in both the control and treated animals. Neovessel dense islands and the interspersed fine network of angiogenic proliferation over the tumor surface are diminished in rabbits receiving the targeted fumagillin treatment. Baseline Images with Regions of Signal Enhancement at 120 Minutes Overlaid Integrin homing ligand αvβ3-targeted peptidomimetic conjugated to PEG(2000)-Phosphatidylethanolamine Cancer MR Imaging Winter et al Cancer Res. 63,5838-5843 Winter et al FASEB Journal. 2008;22:2758-2767.

  27. 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

  28. 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.

  29. Mn Based T1w MR Contrast Agents ManOC ManOC MRI 10 nm ManOL Thermal decomposition ManOL Relaxivities /(s.mmol)_1 A unique way of incorporating heavy payload of metal Average metal /NP = 120,000 Pan et. al, Chemical Communications, 2009, 3234 - 3236

  30. Metal NanoColloids for T1-weighted MRI MR properties are presumably not dependent on the interaction of M with surrounding water! T1w MRI Strong T2 effects Weaker T2 effects Metal Nanoparticle Metal Nanocolloids Fe-Nanocolloids (a) (b) T2*/T2 T1 <T2 Mn(II)-Nanocolloids Metal Cu(II)-Nanocolloids B0 B0 External Magnetic field External Magnetic field Cartoon illustrating hypothesis of decreased T2* effects (a) A typical metal particle surrounded by water within a B0 field. The field dependent dipole moment created is shown. Protons pass deep within this magnetic flux field and experience strong dephasing T2 effects. (b). The encapsulation of metal crystals reduces the effective field experienced by the surrounding protons, such that the relative impact on T2* is greater than the changes of T1 relaxivity. Chem Commun, 2009; ACS Nano 2009; JACS 2011

  31. Copper As MR Contrast Agent MRI detection of fibrin clots in vitro. On T1-weighted cross-sectional images, the clot with Targeted NanoQ (A) shows marked signal enhancement, whereas the controls of Non-Targeted Contrast Agent (B) or No Treatment (C) show little or no enhancement above the background water signal. (D) Normalized contrast-to-noise measurements of targeted and control NanoQ bound to clots with respect to the surrounding fluid. J. Am. Chem. Soc., 2011, 133 (24), pp 9168–9171

  32. Pharmacokinetics and Biodistribution in Rats C(t)=Ae-αt + Be-βt with constants A and α describing the distribution phase, and B and β describing the blood clearance phase.The half-life for the distribution phase was 5.04 ± 1.1 min; elimination half-life was 99.2 ± 10.7 min. Copper organocomplexes were rapidly bio-eliminated primarily through both renal and biliary routes, suggested by the metal concentrations of the kidney and feces ICP-OES analyses of blood and organs for Cu In vivo pharmacokinetics and bio-distribution of NanoQ. (A) pharmacokinetic profile of targeted NanoQ with a bi-exponential fitting (y=0.5903*exp(-0.1374*t) + 0.5205*exp(-0.0070*t). (B) Organ distribution of NanoQ based on copper estimation of major organs by ICP-OES at 2h following NanoQ injection (1mg/ml) i.v.

  33. In vitro and ex-vivo Targeted MRI with CION with anti-Fibrin Antibody CION Control Fibrin-rich Plasma Clots CION CION Rapid T1w Imaging Senpan, Caruthers, Pan, Wickline, Lanza, 2009 ACS Nano

  34. 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

  35. Colloidal Iron Oxide Nanoparticle (CION) 20-30 nm Fe3O4 Cartoon illustrating hypothesis of decreased T2* effects of CION to SPIO (a) A typical iron oxide particle surrounded by water within a B0 field. The field dependent dipole moment created is shown. Protons pass deep within this magnetic flux field and experience strong dephasing T2 effects. (b). The encapsulation of CION iron crystals reduces the effective field experienced by the surrounding protons, such that the relative impact on T2* is greater than the changes of T1 relaxivity. (c) The encapsulation of CION iron crystals with surfactant cross-linking further reduces the effective field experienced by the surrounding protons, such that the impact on T2* is further increased relative to the changes of T1. T1 Contrast Agent! Low susceptibility artifact Senpan et al 2009 ACS Nano

  36. “Holey” Nano-bialys: Targeted MRI agent 20% 100 nm TEM AFM Chemically cross-linked surface to control the release of soluble drugs Mn(III) Contrast agents Dissolution Experiment with soluble and insoluble drugs Fibrin Clot 1.5 T MRI Biotin Targeted Clots • Derived from amphiphilic lipid-polymer hybrid (PEI) • Optionally Cross-linked membrane to control the release of insoluble drugs and stability • Ionic r1=3.7 (s·mmol [Mn])-1 particulate relaxivities • 866 989 (s·mmol [nanobialy])-1 • In adequate signal in vivo Theranostic Agent

  37. In vitro and ex-vivo Targeted MRI with CION with anti-Fibrin Antibody CION Control Fibrin-rich Plasma Clots CION CION Rapid T1w Imaging Senpan, Caruthers, Pan, Wickline, Lanza, 2009 ACS Nano

  38. Dual Modality Optical-MRI Imaging of Integrin a) Schematic illustration of dual-modality RGD targeted iron oxide nanoparticles containing IRDye800 for tumor ανβ3integrin imaging. b) TEM of the 10 nm iron oxide nanoparticles. c) T2-weighted phantom images of targeted agent at increased iron concentrations. d) 1/T2 vs. Fe concentration plot of the targeted agent.

  39. a) MR images of U87MG tumor-bearing mice injected with the RGD targeted dual agent (RGD-TPIO) and the non-targeted agent (TPIO) at a dose of 10 mg Fe/kg. The images were taken both coronally and transversely before and 4 h after particle injection. b) Optical imaging of U87MG tumor-bearing mice injected with RGD-TPIO and TPIO. The images were acquired 4 h hh h post injection. http://www.thno.org/v01p0083.htm

  40. Dual Modality Optical-MRI Imaging of Integrin Schematic representation of the synthesis of QDs with a paramagnetic micellar coating. QDs and lipids in chloroform are slowly infused in hot water that, via chloroform-in-water emulsions, swiftly form micelles when chloroform evaporates, some of which have a Qdot core. In vitro targeting and imaging with QD-micelles. a, left T1-weighted MRI image of cells that were incubated with RGD-pQDs, pQDS, or without contrast agent. a, right Fluorescence microscopy of HUVEC incubated with RGD-pQDs. 

  41. Dual Modality Optical-MRI Imaging of Integrin The schematic structure of αvβ3-integrin targeted micellar nanoparticles for optical and MR imaging (left) and MR and optical molecular imaging of tumor angiogenesis (right). T2-weighted images before the contrast agent was injected (a, e); T1-weighted images before (b, f) and 45 min after (c, g) the injection of the RGD targeted micellar imaging agent and color-coded signal enhancement in tumors (d, h). The arrows in (c, g) indicate bright regions in the periphery of the tumor. Bioluminescence image (i) and fluorescence image (j) of a nude mouse with a luciferase-expressing renal carcinoma tumor after injection of luciferin (i) and the targeted imaging agent (j). The signal colocalizes with a strong fluorescence signal (j) originating from intravenously administrated RGD-pQDs that are accumulated in the tumor.

  42. β-galactosidase Enzym-mediated contrast agent CLIO Ca2+mediatedcontrast agent Gen-sequencespecificcontras 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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