Photothermal Optical Coherence Tomography of Nanoparticle Contrast Agents

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1 Photothermal Optical Coherence Tomography of Nanoparticle Contrast Agents Jason M. Tucker Schwartz Kelsey R. Beavers Craig L. Duvall Melissa C. Skala Vanderbilt University Department of Biomedical Engineering Nashville, TN

2 Preclinical molecular imaging Optical microscopy [2] MRI [4] PET/SPECT [5] 3 μm Photoacoustics [3] [1] Marusyk et al., Nat Rev Cancer (212) [2] Skala et al., Cancer Res (25) [3] De la Zerda et al., Nature Nanotech (28) [4] Lee et al., Nature Med (26) [5] Manning et al., Clin Cancer Res (28) 2

3 Preclinical molecular imaging Imaging spatial heterogeneity in molecular status and uptake dynamics of drugs can help to better understand treatment resistance in cancer [1] High resolution Deep 3-D Sensitive Optical microscopy [2] Photoacoustics [3] [1] Marusyk et al., Nat Rev Cancer (212) [2] Skala et al., Cancer Res (25) [3] De la Zerda et al., Nature Nanotech (28) [4] Lee et al., Nature Med (26) [5] Manning et al., Clin Cancer Res (28) 3

4 Optical coherence tomography (OCT) Tomographic map of axial reflectivity Technology leverages interference of a low coherence broadband source High resolution (~1-1 μm isotropic) Deep optical imaging (1-3 mm) Fast and noninvasive Clinical applications SOC in ophthalmology Intravascular stent imaging Simultaneous 3-D imaging of: Tissue morphology Vessel morphology Vessel flow No inherent strong source of molecular specificity Broadband Light Source Reference Spectrometer k=2π/λ k=2π/λ k=2π/λ k=2π/λ Sample II = 22 EE RR EE SS cccccc(2222 zz + φφ) Fourier Transform z 4

5 Functional imaging with OCT What if we want to image molecular expression or drug uptake with OCT? We need a contrast agent and a mechanism of contrast. 5

6 Functional imaging with OCT Enhanced Backscattering [1] Spectroscopic OCT [2] Passive Detection Magnetomotive OCT [3] Photothermal OCT [4] Active Detection [1] Agrawal et al., Opt Exp (26), [2] Oldenburg et al., J Mater Chem (29), [3] Renu et al., PNAS (21), [4] Zhou et al., Opt Lett (21) 6

7 Research goal Develop and optimize PTOCT of near infrared contrast agents for functional imaging with OCT 7

8 Photothermal OCT (PTOCT) photon absorption local heating index of refraction, elastic expansion OOOOOO = nnnn optical path length OCT phase δδoooooo(tt) = λλ 4ππ δδδδ(tt) Contrast Agent Wavenumber OCT Beam Heat Release Time Amplitude-Modulated Photothermal Beam PTOCT is independent of the scattering background and therefore highly sensitive and specific to the contrast agent. [1] Skala, Nano Letters (28) [2] Adler, Optics Express (28) [3] Zhou, Optics Letters (21) [4] Kuranov, BOE (211) [5] Jung, Nano Letters (211) [6] Guan, JBO (212) [7] Tucker-Schwartz, Optics Letters (212) 8

9 Near infrared absorption Deeper image penetration Minimal background signal Tunable absorption peak Precise control for multiplexing applications Narrow absorption peak Minimal overlap with imaging beam Multiplexing capabilities Distinct shape for spectral measurements Efficient absorption Size scale desirable for tumor delivery Larger than kidney filtration Smaller than tumor vessel pores Conjugation chemistry established Platform technology Gold nanorods (GNRs) are attractive PTOCT contrasts Extinction (a.u.) 1.5 CTAB-coated PEG-coated Wavelength (nm) PEG-coated nanorods (~45.2X13.2 nm) with 725 nm absorption peak 9

10 PTOCT instrumentation and signal analysis Depth (mm) Magnitude (a.u.) Time (ms) Depth (mm) Phase (radians) Time (ms) Amplitude Modulation Phase (radians) Time (ms) FFFF Photothermal Signal (nm) Frequency (Hz) Axial resolution: 6.4 μm Lateral resolution: 8.5 μm (25 μm) Phase sensitivity: ~ 1.5 mrad ~ 13 pm 725 nm, 2 Hz, 1 mw (4 mw) photothermal beam 1 khz line rate Temporally sample (M-mode) while amplitude modulating heating Digitally lock-in to photothermal signal SLD = superluminescent diode (OCT source), 5/5 = 5/5 fiber coupler 1

11 PTOCT signal validation Model [1] Bio-heat conduction equation with heat source term Scattering of pump beam ignored Spot size << 1/μ a (radial heat conduction) Experiments Homogenous liquid GNR sample Perturb image parameters Photothermal laser power Photothermal amplitude modulation frequency OCT image signal GNR concentration αα, ρρ, cc, kk: tttttttttttt pppppppppppppppppppp rr, tt: dddddddddddddddddddd μμ aa : cccccccccccccccc aaaaaaaaaa pppppppppppppppppp PP, ωω, tt LL : cccccccccccccccccccccccc iiiiiiiiii pppppppppppppppppppp GNRs OCT/PT beam coverslip slide [1] van Gemert et al., Phys Med Biol (1996) 11

12 PTOCT signal validation Photothermal model produces temperature dynamics similar to our imaged PTOCT signal [1] van Gemert et al., Phys Med Biol (1996) [2] Tucker-Schwartz et al., Biomed Opt Exp (212) 12

13 PTOCT signal validation Photothermal model produces temperature dynamics similar to our imaged PTOCT signal The PTOCT signal scales linearly with photothermal laser power [1] van Gemert et al., Phys Med Biol (1996) [2] Tucker-Schwartz et al., Biomed Opt Exp (212) 13

14 PTOCT signal validation Normalized Signal (a.u.) Experimental Modeled Chopping Frequency (Hz) Photothermal model produces temperature dynamics similar to our imaged PTOCT signal The PTOCT signal scales linearly with photothermal laser power The PTOCT signal decreases nonlinearly with amplitude modulation frequency [1] van Gemert et al., Phys Med Biol (1996) [2] Tucker-Schwartz et al., Biomed Opt Exp (212) 14

15 The effect of OCT image SNR 12 8 PT-OCT Signal (nm) r 2 =.16 PT-OCT Noise (nm) Change in OCT Magnitude Signal ( db) Change in OCT Magnitude Signal ( db) Mean photothermal signal is independent of OCT image SNR The noise in the photothermal signal increases with weaker reflections, due to decreased phase stability [1,2] OCT SNR PTOCT SNR [1] Choma et al., Opt Lett (25), [2] Vakoc et al., Opt Express (25) [3] Tucker-Schwartz et al., Biomed Opt Exp (213) 15

16 PTOCT sensitivity to gold nanorods 5 PT-OCT Signal (nm) * r 2 =.997 Experimental Scattering control Best Fit Line GNR Concentration (pm) Linear increase in PTOCT signal with GNR concentration Sensitivity to ~7.5 pm concentrations of nanorods (p<.5 compared to liquid scattering control) PTOCT sensitivity < potential nanorod concentrations in vivo [1,2] [1] Agrawal et al., JBO (26) [2] von Maltzahn et al., Cancer Res (29) [3] Tucker-Schwartz et al., Biomed Opt Exp (213) * p<.5 16

17 Solid agarose phantoms 4 pm gold nanorod sample (left) Depth (mm) Depth (mm) Position (mm).5 1 GNR+ GNR- GNR Position (mm) Negligible difference in OCT signals (CNR < 1) ~15X increase in average PTOCT signal with nanorods present ~11X increase in CNR between PTOCT and OCT Contrast enhancement in solid imaging phantoms OCT Signal (a.u.) PT-OCT Signal (nm)5 GNR+ GNR+ GNR- CCCCCC = SS GGGGGG+ CNR =.6 CNR = 6.8 SS GGGGGG σσ GGGGGG [1] Tucker-Schwartz et al., Biomed Opt Exp (213) 17

18 Conclusions [1] Gold nanorods enhance OCT contrast through photothermal heating in phantoms as well as in vivo PTOCT scales with multiple image parameters PTOCT is sensitive to pm concentrations of gold nanorods PTOCT can distinguish gold nanorods from highly scattering background signal in vivo Passive accumulation of nanoparticles in tumors Photothermal OCT of gold nanorods could augment microscopy for preclinical molecular imaging of cancer Deep tissue imaging Depth-resolved High resolution High molecular sensitivity [1] Tucker-Schwartz et al., Biomed Opt Exp (212) 18

19 Acknowledgments Lab Members: Devin McCormack Kristin Poole Michael Schultis Amy Shah Wesley Sit Alex Walsh Dr. Chetan Patil Additional Collaborators: Spencer Crowder Travis Meyer Wesley Sit Victoria Youngblood Dr. Dana Brantley-Sanders Dr. John Stone NCI R CA NHLBI R21 HL19748 Breast Cancer SPORE P5 CA98131 BC Visit us online: VU Discovery Grant VICC Discovery Grant 12GRNT We are currently recruiting graduate students and postdocs; please m.skala@vanderbilt.edu if interested. 19