Experimental modeling of local laser hyperthermia using thermosensitive nanoparticles absorbing in NIR Grachev P.V., Romanishkin I.D., Pominova D.V., Burmistrov I.A., Kaldvee K., Sildos I., Vanetsev A.S., Orlovskaya E.O., Orlovskii Yu.V., Loschenov V.B., Ryabova A.V. Prokhorov General Physics Institute, Russian Academy of Sciences, Moscow, Russia Institute of Physics, University of Tartu, Tartu, Estonia This work was supported by MES RF: RFMEFI61615X0064

Hyperthermia therapy At the moment, there exist several ways of using hyperthermia as treatment of cancers. The use of systemic and regional hyperthermia increases the effectiveness of chemotherapy and radiotherapy techniques. The method of local laser hyperthermia can be used independently, and have a direct effect on individual tumor cells and organelles.

Localized hyperthermia Pulse time from pico- to nanoseconds The use of special thermal agents helps minimizing the overheating of the healthy tissue as well as maximizing the destruction of tumor. Such agents can be magnetic and plasmon nanoparticles, nanoparticles doped with rare earth ions, and quantum dots. As a result of local heating, the apoptotic mechanism of cell death could be triggered, leading to a gradual replacement of the dying tumor cells with healthy tissue. τ τ τ∼ps τ∼ns Biomolecule Dy3+ Tm3+ Nd3+ Biostructure Visualization of the nanoparticle pulse laser excitation with subsequent environment heating

nanoparticles, biomolecules Heat localization The use of pulse laser excitation results in more localized heating The temperature distribution surrounding a gold nanoparticle (calculations) Pulse length Effective radius Target types 1 sec 350 mm 1 ms 10 mm cells, capillaries 1 us 0.35 mm cell organelles 1 ns 10 nm nanoparticles, biomolecules 1 ps 0.3 nm clusters 1 fs 0.1 A molecules Spatial distribution of temperature in the gold nanoparticle environment depending on the excitation pulse length [1] The depth of thermal effect depending on the excitation pulse length (calculations) 1 Hüttmann et al. High precision cell surgery with nanoparticles? Medical Laser Application, 2002

The main disadvantage of existing devices for temperature determination – that temperature is measured from the surface while the temperature in the tissue depth remains unknown.

Light transfer in media Scheme of light propagation in a scattering medium Main absorbers in biotissue

Composite nanosystems based in the crystalline nanoparticles doped with plasmonic nanoparicles and Dy3+ и Nd3+ rare-earth ions for photohyperthermia with the capability for fluorescent navigation and non-invasive temperature determination based on their spectral characteristics Plasmon Nanoparticle YPO4:Dy3+ LaF3:Nd3+ Particles were synthesized in Institute of Physics, University of Tartu, Estonia YPO4:Dy3+

Fiber-optic probe with cooling Fiber-optic probe 3D-model The experimental setup for optical phantom temperature measurements The distance between the receiving fiber and the probe center: 1.5 – 2.5 см Receiving fiber angle of incidence to the phantom surface: 0˚, 30˚, 45˚

Rare-earth luminescence spectrum registration LFT-805-01-BIOSPEC laser system (Biospec, Russia) with fiber-optic delivery light Raman-HR-Tec fiber-optic spectrometer (StellarNet, США) YPO4:Nd3+ nanoparticle luminescence spectrum with decomposition into Stark components

Temperature registration Simultaneously, the temperature of the biotissue phantoms was been measured using the thermal IR camera JADE MWIR SC7300M (CEDIP, France). The data obtained with the thermal camera was compared with calculated from luminescence spectra

Mathematical modeling of light propagation Scattering pattern of laser radiation with a wavelength of 805 nm in pseudocolor. The distance between the fibers is 5 mm, the angle is 45 degrees relative to the normal to the surface of the tissue Sounding depth, mm The plot of the depth of sounding from the angle of inclination of the fibers relative to the normal to the biotissue at a fixed distance between the fibers of 20 mm, the wavelength of the laser radiation is 810 nm. Angle, ˚

The most probable photon path (red color) Scattered laser (805 nm) The most probable photon path (red color) Sounding depth, mm Distance between fibers, mm

Scattered laser light intensity Intensity, a.u. Intensity, a.u. Lipofundin concentration, % Distance, mm Dependence on the concentration of the scattering medium for different positions of the receiving fiber Dependence on the distance between fibers for different concentration of the scattering medium

Luminescence and scattered laser light intensity Интенсивность лазерного излучения планируется использовать для оценки степени коагуляции Lipofundin concentration 0.4% The distance between illuminating and receiving fibers was 25 mm

Spectroscopic evaluation of Nd3+ nanoparticles local temperature Temperature values obtained using IR thermal camera Temperature values calculated from the luminescence spectra

Temperature values obtained using IR thermal camera Temperature values calculated from the luminescence spectra

Summary A fiber-optic probe with cooling has been developed, which makes it possible to obtain a luminescent signal from various depths by changing the position and angle of inclination of the receiving optical fiber, and also cause laser-induced heating of optical models of tumors. The optimal position and angle of inclination of the receiving optical fiber for different depths of the tumor model are determined. Demonstrated mismatch between the temperature measured from the surface using thermal IR camera and the actual temperature at the depth measured spectroscopically.

Thank you for your attention