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Quantitative Oxygen Imaging with Electron Paramagnetic/Spin Resonance Oxygen Imaging Howard Halpern
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Why EPR? Bad News: native diffusible unpaired electrons: Rare Good News: rare native electrons mean no background signal Bad News: Need to infuse subjects with materials with stable unpaired electrons Good News: Can infuse materials which target pharmacologic compartments
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Why EPR? Spectroscopic Imaging: Specific quantitative sensitivity to Oxygen, Temperature, Viscosity, pH, Thiol Each property of interest is measured with a specifically designed probe. Free Radicals can be detected as well
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Why EPR? Spectroscopic Imaging: Specific quantitative sensitivity to Oxygen, Temperature, Viscosity, pH, Thiol No water background for signal imaging (vs MRI)
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Why EPR? Spectroscopic Imaging: Specific quantitative sensitivity to Oxygen, Temperature, Viscosity, pH, Thiol No water background for signal imaging (vs MRI) Deep sensitivity at lower frequency (vs optical) 250 MHz vs 600 THz, 6 orders of magnitude lower 7 cm skin depth vs < 1 mm Vs typical EPR (0.009T vs 0.33T electromagnet) 250 MHz vs 10 GHz, factor of 40 lower 7 cm skin depth
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Why Electron Paramagnetic (Spin) Resonance Imaging? More sensitive and specific reporter of characteristics of the solvent environment of a paramagnetic reporter The reporter can be designed to report (mostly) only one characteristic of the environment E.G.: oxygen concentration, pH, thiol concentrations We have chosen to image molecular oxygen.
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Basic Interaction Magnetic Moment let bold indicate vectors) Magnetic Field B Energy of interaction: – E = -µ∙B = -µB cos(θ)
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Magnetic Moment ~ Classical Orbital Dipole –Orbit with diameter r, area a = πr 2 –Charge q moves with velocity v; Current is qv/2πr –Moment µ = a∙I = πr 2 ∙qv/2πr = qvr/2 = qmvr/2m mv×r ~ angular momentum: let mvr “=“ S β = q/2m; for electron, β e = -e/2m e (negative for e) µ B = β e S ; S is in units of ħ –Key 1/m relationship between µ and m µ B (the electron Bohr Magneton) = -9.27 10 -24 J/T
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Magnitude of the Dipole Moments Key relationship: |µ| ~ 1/m Source of principle difference between –EPR experiment –NMR experiment This is why EPR can be done with cheap electromagnets and magnetic fields ~ 10mT not requiring superconducting magnets
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Major consequence on image technique µ electron =658 µ proton (its not quite 1/m); Proton has anomalous magnetic moment due to “non point like” charge distribution (strong interaction effects) m proton = 1836 m electron Anomalous effect multiplies the magnetic moment of the proton by 2.79 so the moment ratio is 658
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The Damping Term (Redfield) ∂ρ*/∂t= 1/iћ [H*(t’) 1, ρ*(0)]+ 0 (1/iћ) 2 ∫dt’[H* 1 (t),[H* 1 (t-t’), ρ*(t’)] Each of the H* 1 has a term in it with H= -µ∙B r and µ ~ q/m ∂ρ*/∂t~ (-) µ 2 ρ* This is the damping term: ρ*~exp(- µ 2 t with other terms) Thus, state lifetimes, e.g. T 2, are inversely proportional to the square of the coupling constant, µ 2 The state lifetimes, e.g. T 2 are proportional to the square of the mass, m 2
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Consequences of the Damping Term The coupling of the electron to the magnetic field is 10 3 times larger than that of a water proton so that the states relax 10 6 times faster No time for Fourier Imaging techniques For CW we must use 1.Fixed stepped gradients 1.Vary both gradient direction & magnitude (3 angles) 2. Back projection reconstruction in 4-D
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Imaging: Basic Strategy Constraint: Electrons relax 10 6 times faster than water protons Image Acquisition: Projection Reconstruction: Backprojection
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Projection Acquisition in EPR Spectral Spatial ObjectSupport ~
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=α=α
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Projection Description With s(B sw, Ĝ) defined as the spectrum we get with gradients imposed
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More Projection The integration of f sw is carried out over the hyperplane in 4-space by Defining with The hyperplane becomes with
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And a Little More So we can write B = B sw + c tanα Ĝ∙x
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So finally it’s a Projection with
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Projection acquisition and image reconstruction Image reconstruction: backprojections in spectral-spatial space Resolution: δx=δB/G max THUS THE RESOLUTION OF THE IMAGE PROPORTIONAL TO δB each projection filtered and subsampled; Interpolation of Projections: number of projections x 4 with sinc(?) interpolation, Enabling for fitting Spectral Spatial Object Acquisition: Magnetic field sweep w stepped gradients (G) Projections: Angle : tan( =G* L/ H
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The Ultimate Object: Spectral spatial imaging
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Preview: Response of Symmetric Trityl (deuterated) to Oxygen So measuring the spectrum/spectral width≈relaxation rate measures the oxygen. Imaging the spectrum: Oxygen Image
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Why is oxygen important in cancer?
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Known Since 1909 but in 1955 Thomlinson and Gray showed necrosis viable tissue
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Dramatic differences in survival for patients with cervical cancer treated with radiation depending on mean tumor oxygenation: > or < 10 torr Hockel, et al, Ca Res 56 (1996), p 4509
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This was thought to be the source of radiation resistance Hyperbaric oxygen trials √ (in human trials) Oxygen mimetic radiosensitizers √ (in animals only due to toxicity) Eppendorf electrode measurements (humans)
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Intensity Modulated Radiation Therapy Sculpts radiation dose over distances of 5mm Able to spare normal tissues But tumor volumes are homogeneous; no accounting for different regions with different sensitivity
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Biological imaging to enhance targeting of radiation therapy: oxygen imaging Intensity modulated radiation therapy allows sophisticated control over spatial distribution of radiation dose
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Biological imaging to enhance targeting of radiation therapy: oxygen imaging Intensity modulated radiation therapy allows sophisticated control over spatial distribution of radiation dose But: some regions may contain hypoxic cells
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Biological imaging to enhance targeting of radiation therapy: oxygen imaging Hypoxic cells are known to be radioresistant 0.0076 torr 0.075 torr 0.25 torr 1.7 torr Air
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Biological imaging to enhance targeting of radiation therapy: oxygen imaging Intensity modulated radiation therapy allows sophisticated control over spatial distribution of radiation dose Areas of hypoxia could be given extra dose if only we could identify them! So...
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Why use radio-frequency for EPR? 250 MHz ~ 6 T MRI S/N N~ 1.2 IN LOSSY, CONDUCTIVE TISSUE
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Aim: Image crucial physiologic information:oxygen Information: Communicated by reporter molecules which are injected into animals/humans. Communication through EPR spectrum. Simple spectrum in a complex biological system
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Response of Symmetric Trityl (deuterated) to Oxygen No temp. dependence: < 0.05 mG/K Low viscosity dependence ~1mG/cP Self quenching a potential confounding variable -- Solved with Longitudinal Relaxation Rate Imaging
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Information about fluid in which reporter molecule dissolved obtained from Spectral Parameters Spectral parameters extracted from spectral data using Spectral/Relaxation Rate Fitting Bonus: Fitting gives parameter uncertainties Standard penalty for deviation: χ 2 =(y i -fit(x i, a j )) 2 minimize this penalty by adjusting the Spectral Parameters a j e.g., spectral width … spectral width
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Major improvement: Synthesis of selectively deuterated OX31 Improves 1. Oxygen sensitivity: B R/R Spatial resolution for a given gradient: resolvable x= B/G 3. Sensitivity d d
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Line widths pO 2 calibration Oxygen dependence of spin packet width obtained in a series of homogenous solutions of OX31: Since minimal viscosity dependence, aqueous=tissue
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CW 4D IMAGE LINEWIDTH RESOLUTION A measure of the line width resolution is the distribution of linewidths from a homogeneous phantom. Here, the of the distribution is 0.17 T, or ~ 3 torr pO 2 (8x8x8,projections in 20 minutes)
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Line Width Fidelity: Agreement Between Image and Individually measured line-widths (1.6 mm) heterogeneous phantom. Side lines Approximately ±3 torr.
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EPR spectral-spatial 4D imaging CW EPR imager at 250 MHz, with a loop-gap resonator
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Dimensions of the resonator (1.5 cm thick) Sensitive Region of the resonator (total of just over 2 -2.5 cm)
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Mouse Image (OX063) XY YZ PC3 tumor with 3D intensity image (Note no artifacts surrounding surface) XY and YZ pO2 slices corresponding to the slices in the volume
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Oxylite probe Into tumor Validation with Oxylite fiberoptic probe (measuring fluorescence quenching by oxygen) Stereotactic Platform For Needle Location
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Good agreement!
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Adjacent tracks in areas of rapid oxygen variation agree with Oxylite
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New insight into the oxygen status of tumors and tissues
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