Precise determination of the heat delivery during in vivo magnetic nanoparticle hyperthermia with infrared thermography

Transcription

1 Precise determination of the heat delivery during in vivo magnetic nanoparticle hyperthermia with infrared thermography Harley F. Rodrigues 1, PhD; Gustavo Capistrano 1 ; Francyelli M. Mello 2 ; Nicholas Zufelato 1 ; Elisângela Silveira-Lacerda 2, PhD; Andris F. Bakuzis 1, PhD. 1 Institute of Physics, Federal University of Goiás - Brazil 2 Institute of Biological Sciences, Federal University of Goiás - Brazil

2 Outline Motivation Magnetic Nanoparticle Hyperthermia (MNPH) Noninvasive Thermometry Murine tumor model of Sarcoma 180 Characterization of the MNP of MnFe 2 O 4 DMSA Experimental setup Experimental results Theoretical model to correct IR measurements Real time evaluation of the intratumoral heating using IRT of the skin surface Experimental setup Experimental results Two-dimensional infrared mapping relating the heating profile of the skin with the average intratumoral temperature. Conclusions and Perspectives Acknowledgments

3 Motivation In vivo Magnetic Nanoparticle Hyperthermia (MNH): Magnetic Fluid Normal Temperature AC Current Alternating Magnetic Field Tumor Temperature Elevation Rotation of the magnetic moments of the nanomagnets

4 Noninvasive Thermometry (A) (C) (B) T MAX = 41,2 C t = 5 min

5 Noninvasive Thermometry Magnetic Resonance Thermometry Ultrasound Thermometry 5

6 Noninvasive Thermometry Magnetic Nanothermometry Fluorescent nanothermometers

7 Noninvasive Thermometry

8 Materials and methods

9 Sarcoma 180 (A) (B) Subcutaneous inoculation S180 cells grow in ascitic form in the peritoneal cavity (C) cells (cell viability 90%) Induction of the solid and subcutaneous tumor (S180)

10 Sarcoma 180 Palpable Tumor Daily monitoring of tumor growth Major Axis (D) Minor Axis (d) in vivo tumor volume equation (mm 3 ): V ex vivo tumor 5

11 MNP of MnFe 2 O 4 DMSA Count (A) (B) (C) D = (15 ± 3,0) nm Diameter (nm) MnFe 2 O 4 - DMSA LogNormal Fitting Intensity (a.u.) 600 MnFe 2 O 4 - DMSA D XR = (14,1 ± 2,1) nm Angle (2θ) Intensity (%) 28 MnFe 2 O 4 - DMSA 24 D HD = 64.2 nm Diameter (nm) Magnetization (emu/g) (D) (E) (F) MnFe 2 O 4 - DMSA (dust) - TGA: 900 C M dust = 58,4 emu/g H (Oe) Sample mass (%) Temperature ( C) MnFe 2 O 4 - DMSA Zeta Potential (mv) ph MnFe 2 O 4 - DMSA

12 Experimental setup (A) (B) Eixo z (eixo da bobina) (mm) Plano y = 0 B 220 G Campo magnético B (G) f = 301 khz 140 G 180 G 220 G 260 G 300 G 340 G 380 G 420 G (C) (D) Magnetic Fluid Temperature ( C) Eixo x (mm) MnFe 2 O 4 - DMSA 35 B 220 G (17.5 KA/m) 30 f = 301 khz V MF = 90 µl 25 SLP in vitro = W/g Time (s)

13 Experimental setup Three different injection sites (30 each one) 5.0 mm V FM = 90 L de FM: MnFe 2 O 4 DMSA: m NP = 2.3 mg

14 Precise determination of the heat delivery during in vivo MNPH with IRT

15 θ = 30 t = 31 min Skin surface temperature over the tumor region ( C) Animal #2: θ = 30 Probe on tumor (Skin) IR Cam (θ = 30 ) Rectum temperature Time (min)

16 Protocol: 5 hyperthermias (150 min) Heating 30 min Magnetic Field off 20 min Heating 30 min

17 θ = 0 θ = 15 θ = 30 θ = 45 θ = 60 1 st Heating (t = 30 min) 2 nd Heating (t = 30 min) 3 rd Heating (t = 30 min) 4 th Heating (t = 30 min) 5 th Heating (t = 30 min) T probe T IR Cam ( C) Animal #1 θ = 0 θ = 15 θ = 30 θ = 45 θ = Time (min) T probe T IR Cam ( C) Animal #2 θ = 60 θ = 45 θ = 30 θ = 15 θ = Time (min)

18 T sonda T IR Cam ( C) Animal #1 θ = 0 8 Animal #2 θ = 15 θ = 30 7 = θ = 45 6 Animal θ = 0 θ = θ 15 = 60 θ = 30 5 θ = 45 θ = 60 T probe T IR Cam ( C) θ = 60 θ = #1 1.3 C 2.9 C 3.0 C C 4.7 C 2 2 θ = 30 #2 0.5 C 1.4 C 2.2 C 5.5 C 7.3 C θ = * Average difference calculated from the fifth minute 0 of tumor heating after the θ = temperature data acquired over the tumor skin surface -1reached a quasi-stationary regime Time (min) Time (min)

19 (A) (B) (C) I e (λ, θ, φ, T) The blackbody spectral intensity: Directional Spectral Intesity emitted from a real body:, 2 1,,,,,, Ω The Stefan-Boltzmann law: Hemispherical Spectral emissive power,, : 1 /,,,,, Ω

20 (A) (B),,,,,, 1 According to the Kirchhoff s law about emitted and incident radiation:,,,,,, 1,, Spectral Directional emissive power emitted from a real surface:,, 1

21 Directional emissivity ε (θ) 1,1 1,0 0,9 0,8 0,7 0,6 0,5 0,4 0,3 0,2 0,1 0,0 ε 0 = 0,98 λ = 10 µm α = 638,37 cm -1 κ = 0,0508 n = 1,33 Human epidermis Direction of emission of thermal radiation - θ Spectral Directional Emissivity:, 1,, 2 where,, 2 2, Extinction coefficient: 4 Complex refractive index: 1 1 1

22 Watmough model (1970): Clark model (1976): where, ; 1 where, uses an approach proposed by Dreyfus (1963): Directly assumes Stefan-Boltzmann's law: Δ 1

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24 T probe T IR (θ) ( C) Average of the experimental error (n = 2) Watmough model (λ = 10µm, κ = ) Clark model (λ = 10µm, κ = ) IRcam objective direction (θ) Watmough (1970) Clark (1976) 1 1

25 Termografia por infravermelho Near infrared NIR (0,75 3,0 µm) Middle infrared MIR (3,0 6,0 µm) Long wave infrared LWIR (6,0 25,0 µm)

26 Our model:,,,,, 1, 1 1, 1 if 1, and 7,5 13,0 µm, 1, 1 I) If e 1, then:, 1, 1, 1,, II) If 1, then:,, 1, and:, 1, III) General solution: 1, 1

27 T probe T IR (θ) ( C) Average of the experimental error (n = 2) Watmough model (λ = 10µm, κ = ) Clark model (λ = 10µm, κ = ) Our model (λ = 10µm, κ = ) IRcam objective direction (θ) Watmough model (1970) Clark model (1976) Our model (2017): 1 1 1, 1

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29 Real time evaluation of the intratumoral heating using IRT of the skin surface

30 Experimental setup Skin temperature Infrared Câmera Intratumoral temperature Up to 03 optical fibers inserted into the tumor 30 Magnetic Hyperthermia 17,5 / ; 301 Skin Temperature on Tumor Region ( C) Probe on the tumor 30 IR Cam (θ = 0 ) Probe inside Rectum Time (min) θ = 0

31 Intratumoral measurements vs Surface IRT Intratumoral temperature (optical fiber) History of heat exposure Identification Probe #1 Probe #2 Probe #3 Probe #1 Probe #2 Probe #3 Animal Tumor Injected Time of d T 0 Volume MNP MNPH ( C) ; T f ( C) T d T 0 ( C) ( C) T f ( C) T d T 0 ( C) ( C) T f ( C) T d t ( C) (min) T ave d t T ave d t T ave ( C) (min)( C) (min)( C) #7 997 mm mg 30 min # mm mg 30 min # mm mg 30 min # mm mg 30 min

32 Intratumoral measurements vs Surface IRT (A) Temperature ( C) (B) Temperature ( C) Animal #7 Optical fiber: Intra #1 Intra #2 Intra # Animal #9 t (min) t (min) Optical fiber Intra #1 Intra #2 Intra #3 (C) Temperature ( C) (D) Temperature ( C) Animal # Animal #10 t (min) Optical fiber Intra #1 Intra #2 Intra # t (min) Fibra-óptica Intra #1 Intra #2 Intra #3

33 Evaluating intratumoral heating using IRT of the skin surface Animal #7: t = 30 min of MNPH, ROI Tumor = (30 40) = 1200 px (A) (B) (C) (1) (1) (2) (2) (3) (3) Which set of values (pixels) carries the important information?

34 Evaluating intratumoral heating using IRT of the skin surface (A) (B) (1) (C) (1) (2) (2) (3) (3) Time (min) IR image pixels inside of the ROI Tumor Px (1) Px (2) Px (3) Px (N) T10% (i) ( C) T50% (i) ( C) T90% (i) ( C) 1 T 11 T 12 T 13 T 1N T10 (1) T50 (1) T90 (1) 2 T 21 T 22 T 23 T 2N T10 (2) T50 (2) T90 (2) t i T i1 T i2 T i3 T in T10 (i) T50 (i) T90 (i) Adapted from: Oleson et. al, 1993, p. 290.

35 Evaluating intratumoral heating using IRT of the skin surface (A) Animal #7 (B) Animal #8 Temperature ( C) % = 3.8 % Intratumoral average (03 probes) T 10% inside ROI TUMOR (skin) Temperature ( C) % = 5.0 % Intratumoral average (03 probes) T 10% inside ROI TUMOR (skin) (B) Animal #9 t (min) (D) Animal #10 t (min) Temperatura ( C) % = 1.3 % Intratumoral average (03 probes) T 10% inside ROI TUMOR (skin) Temperature ( C) % = 1.3 % Intratumoral average (03 probes) T 10% inside ROI TUMOR (skin) t (min) t (min)

36 Conclusions I. For subcutaneous tumors, IRT of the skin allows to distinguish non-specific heating caused by eddy currents from the localized heat delivered by the MNP. II. Right positioning of the IRcam (at 0 ) allows a correct evaluation (with an error~ 0,5 C) of the skin temperature over the subcutaneous tumor region. III. New analytical model about the error (for an IRcam) was developed using the Planck spectral distribution and the new equation is valid even when. Indeed showing the range of Clark equation validity (only when ). IV. Comparing intratumoral temperature values (measured in three points) with the heat detecting on the tumor skin surface (by IRT) was experimentally observed that the percentil matches the average temperature value inside the tumor (with an error~ 5 %).

37 Perspectives I. Experimental correlation between (at the skin surface) and the average temperature inside the subcutaneous tumors needs to be checked with more animals and to be investigated in other solid tumors types (e.g. ehrlich). II. We need to develop or to use experimental technics (e.g. MRI and CT) to determine tridimensionally the volume occupied by MNP (heat centers) after injection inside the tumor. III. With this information and an adequate representation of the tumor and the animal s body (morphology, blood perfusion rate, different tissue conductivities and etc.) we believe that it is possible to solve numerically the bioheat Pennes equation and calculate the in vivo SLP (3D value). By matching the calculated temperature values with the heating profile detected on the surface of the skin by IRT (within the ROI Tumor ).

38 Acknowledgements Prof. Andris Figueiroa Bakuzis, PhD and the Prof. Elisângela de Paula Silveira Lacerda, PhD. Laboratory of Molecular Genetics and Human Cytogenetics (ICB/UFG). This study was supported by: Contact: