Photothermal and photodynamic effects at laser heating with gold nanoparticles and nanocomposits Au-SiO2-Hp Georgy S. Terentyuk1,3, Alla B. Bucharskaya1, Andrey V. Ivanov2, Elina A. Genina3, Alexey N. Bashkatov3, Irina L. Maksimova3, Valery V. Tuchin3, Boris N. Khlebtsov4, Nikolay G. Khlebtsov4 1Saratov State Medical University n. a. V.I. Razumovsky, Saratov 2Russian Cancer Research Center n. a. N.N. Blokhin , RAMS, Moscow 3Saratov State University n. a. N.G. Chernyshevsky, Saratov 4Institute of Biochemistry, Physiology of Plants, Microorganisms RAS, Saratov Saratov Fall Meeting 2012

Determination of gold by atomic absorption spectroscopy gold accumulation in organs 24 hrs after intravenous injection brain kidneys lungs liver spleen blood control 15 nm 50 nm 160 nm Au, μg/mL Atomic -adsorbtion Spectrometr AAS-3 (С. Zeiss) with lamp LT-6М Ashing с H2SO4 t=630оС Resonance line 242,8 nm Detection limit 0,02 μg/ml Range of the linear region 0,2-20,0 μg/ml Terentyuk et al. 2009, No. 5, 292-302

Dynamics of gold concentrations in tumor tissue intertwined after intravenous injection of gold nanoparticles Dynamics of gold concentration in blood after intravenous injection of gold nanoparticles Au, μg/mL t, min t, hrs ○- control, ●- tumor,  - skin and muscle tissue

The value of tumor vascularization for the passive delivery of nanoparticles

Size-dependent changes in the organs 24 hours after intravenous injection of gold nanoparticles brain blood separation

Transparency window of biological tissues Setting resonances Transparency window of biological tissues Extinction Wavelength, nm Epidermis Dermis Hypodermis UV Vis NIR Gold nanoparticles synthesized in the laboratory of biosensors and nanoscale structures of IBPPM RAS, Saratov, Russia

Comparative dynamics of heating of gold nanoparticles solutions Temperature, oC Time, min 0.5 Wt/cm2 0.25 Wt/cm2

С – nanocages, R - nanorods The concentration of gold per gram of tissue a day after the intravenous administration Au, μg/g control tumor muscle liver spleen С – nanocages, R - nanorods

Laser thermolysis of transplanted Ehrlich tumor in mice T, °C Time of heating, min intratumoral intravenous control 720 μg/mL 90 μg/mL Intravenous 400 μg/mL Intravenous 50 μg/mL

The maximum temperature on the surface after laser heating b The kinetics of laser heating of the tumor (1) and health (2) tissues in its maximum one day after intravenous injection of gold nanorods at 2 (a) and 8 mg / kg (b). Curves 3 is the kinetics of maximum heating of healthy tissue without introducing nanoparticles (control)

The temperature distribution on the surface of the animal's skin with intravenous injection of nanoparticle - surface laser heating of the tumor T, °C 0 - before heating; 1-5 after 1-5 minutes after the start of heating, respectively; 6-8 after 1-3 minutes after the heating, respectively

Control - heating without nanoparticles, in a day Experiment - heating with nanoparticles in a day

Transplanted Ehrlich tumor -external irradiation experiment control 1 min 5 min 0 min

Interstitial hyperthermia with nanorods using a catheter with a fiber diffuser Р=1.5 Vt t=15 min L=10 mm

With gold nanoparticles Pathology of tumor tissues after controlled laser thermolysis using plasmon-resonant gold nanoparticles Tissue of transplanted rat kidney cancer before exposure hematoxylin-eosin stain Increase Х150 Without nanoparticles With gold nanoparticles Tumor tissue after laser exposure

A day after tumor transplantation Growth dynamics of subcutaneously transplanted kidney cancer in rats before and after laser hyperthermia, CW, 1 Watt, 30 min Tumor size, cm3 A day after tumor transplantation Laser action thermogram of tumor without nanoparticles ○ - control, ■ - laser heating without nanoparticles ▲ - laser heating after intravenous injection of nanoparticles , 1 ml  - laser heating after interstitial injection of nanoparticles, 0.2 mL thermogram of tumor interstitial introduction of nanoparticles to a depth of 7 mm

Dependence of the mean tumor volume on the number of days passed after PPTT Tumor volume, cm3 Number of days experimental groups with doses of administered gold nanorods: 8 (1) and 2 mg / kg (2), control groups under laser irradiation without introducing nanoparticles (3) and without laser irradiation (4)

Nanocomposites: vitrified gold-silver nanocages modified Yb-HP

Au-NR-SiO2-HP IR-laser ~2.3 Wt/cm2 He-Ne laser ~160 mWt/сm2 Tumor before exposure (V= 3 сm3) Tumor (20 min of exposure) Tumor after 72 hours (V= 0.16 сm3)

Three variants of the protocol for Au-NR-SiO2-HP PTD→12 hours→LTT a) absence of optical postthermal obstacles b)exclusion of thermal effects c) hemostasis (2-12 hours): it is benefit for thermotherapy as heat loss reduces d) decrease in the partial pressure of oxygen and pH increases thermal sensitivity e) LTT inhibits repair of necrotic cells PTD + LTT LTT accelerates chemical reactions Synergistic effects on blood vessels (stasis, collapse) Synchronicity subsequent processes in the tumor tissue LTT→24 hours→PDT a) direct necrosis b) hemostasis - partial reduction of oxygen and pH c) 24 hours restore of blood flow d) 24 hours - pic HSP70 e) resumption of protein synthesis 12-26 hours f) PDT inhibits repair of cells 1) the size of tumors < 3 cm3 2) Temperature 50-75 °C - to avoid the formation of coagulation optical barrier

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