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Novel protocols for PDT treatment under optical monitoring

This research paper discusses novel protocols for photodynamic therapy (PDT) treatment using optical monitoring techniques. It covers topics such as Monte Carlo PDT planning, dual-wavelength fluorescence monitoring, optical coherence tomography, and the response of normal tissue to PDT regimens. The paper also discusses the potential applications of PDT in different medical fields and the development of personalized PDT protocols.

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Novel protocols for PDT treatment under optical monitoring

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  1. Novel protocols for PDT treatment under optical monitoring M.Yu. Kirillin1, A.V. Khilov1, D.A. Kurakina(Loginova)1, E.A. Sergeeva1, V.V. Perekatova1, M.A. Shakhova1,2, A.E. Meller1,2, D.A. Sapunov1,2, A.V. Shakhov2,1, N.Yu. Orlinskaya2,1, and I.V. Turchin1 1Institute of Applied Physics RAS, Nizhny Novgorod, Russia, 2Privolzhsky Research Medical University, Nizhny Novgorod, Russia Saratov Fall Meeting 2018, Saratov, Russia, 25-28 September, 2018

  2. Outline • Motivation • Photodynamic therapy (PDT) • Monte Carlo PDT planning • Simulation of light dose distribution • Dual-wavelength fluorescence PDT monitoring • PS photobleaching monitoring with fluorescence imaging • Optical coherence tomography (OCT) • Response of normal tissue to PDT regimens: animal study • OCT monitoring of pharynx antimicrobial photodynamic therapy • Conclusions

  3. Motivation • Perspectives of photodynamic therapy in different medical applications • Chlorin-based photosensitizers • Optimized PDT protocols • Personalized medicine: novel diagnostic techniques for PDT-monitoring • Low-dose PDT for treatment of chronic inflammatory diseases and for aesthetic medicine • Development of personalized PDT protocols employing optical monitoring

  4. Photodynamic therapy (PDT) • Selective delivery of photosensitizer (PS) • Illumination at PS absorption peak wavelength • Photo-induced generation of singlet oxygen and free radicals • Selective cytotoxic effect • Suppression of pathologic processes and abnormal cells apoptosis

  5. Chlorin based photosensitizers • Benefits: • Fast delivery (~ 0.5-2h) • Fast biodegradation (~ 24h) • High quantum yield of singlet oxygen • Two absorption peaks Chlorin e6 absorption spectrum Dual-wavelength probing can provide additional information

  6. Monte Carlo simulations for PDT planning Principle of Monte Carlo technique Optical properties of tissue layers • MATLAB-based code • Simultaneous processing of 107-108 photons • 3D mapping of fluence and absorbed • dose • 3-layer model of skin • 1-layer model of mucosa D.A. Loginova, et al, J. Biomedical Photonics & Eng, 3(1), 010303 (2017).

  7. Monte Carlo PDT planning l = 405nml= 660 nm Multilayer skin model Mucosa model M. Shakhova, et al,J. Biomed. Opt. (2018) 11 September, 16:15, Room C, D. A. Loginova, “Monte Carlo based dual wavelength PDT planning”

  8. Accumulated absorbed dose: Monte Carlo simulations Dose: 50J/cm2 Multilayer skin model Mucosa model

  9. Comparative analysis of PDT regimens: animal study Object under study PDT regimens Inner surface of rabbit ear @ 405 nm: 50,75, 100, 150 J/cm2 @ 660 nm: 50,75, 100, 150 J/cm2 @ 405+660nm: 50+50, 75+75J/cm2 Monitoring modalities Dual-wavelength fluorescence imaging Optical coherence tomography IR temperature measurements Photosensitizer PS “Revixan derma” (Revixan Ltd., Russia) containing 0.1% of pure chlorin e6 Topical application of 0.03 mm3 of PS to the treatment area of 2x3 cm2 Histologic verification in 1,4 and 7 days after PDT procedure hematoxylin & eosin staining Mallory staining for elastin and collagen Xi-65 staining for young endothelial cells Irradiation Illumination system for PDT “Harmony” (Russia) Intensities: 0.1-0.4 W/cm2 @ 405 nm, 0.1-0.4 W/cm2 @ 660 nm

  10. Dual-wavelength PS fluorescence monitoring Custom-built setup for PDT monitoring “Fluovizor”* serves as an indicator of fluorescent layer thickness d The difference in optical properties** of tissue and PS provides the information about fluorescent layer thickness * M. Kleshninet al., Laser Phys. Lett., 12(11), 2015. ** A. Khilov et al., CTM, 9(4), 2017. 13 September, 15:50, Room C, A.V. Khilov

  11. Dual-wavelength fluorescence imaging Typical kinetics of fluorescence signal Evolution of signal ratio Rabbit ear PDT l = 405nm, Dose: 50J/cm2 excitation @ 405nm excitation @ 660 nm • Signal decay indicates PS photobleaching during procedure • Signal ratio kinetics indicate photobleaching of upper layers followed by deeper photobleaching

  12. Optical coherence tomography OCT-1300E OCT-1300U • - spectral-domain OCT • - contact en-face OCT-probe - central wavelength @1280 nm, • - in-depth resolution (in air) 15 mm, • - transversalresolution 15mm, • frame acquisition rate: 25 fps • 3D imaging • OCT-angiography • - time-domain OCT • - flexible endoscopic en-face OCT-probe with angular scanning • - central wavelength @1280 nm, • - in-depth resolution (in air) 15 mm, • - transversalresolution 30mm, • - frame acquisition rate: 8-10 fps 1 mm V.M. Gelikonovet al, Laser Physics,13(5), 692-702 (2003). A. Moiseevet al, J. Biophotonics,e201700292 (2018).

  13. OCT monitoring of PDT: effect of dose before after in 1 day in 4 days in 7 days Rabbit ear PDT l = 405nm, Dose: 50J/cm2 In-depth En face Angiography

  14. OCT monitoring of PDT: effect of dose before after in 1 day in 4 days in 7 days Rabbit ear PDT l = 405nm, Dose: 150J/cm2 In-depth En face Angiography

  15. OCT monitoring of PDT

  16. Histologic verification: effect of color controlPDT@ 405 nm: 50 J/cm2 PDT@ 660 nm: 50 J/cm2 H & E no edema manifestation edema from irradiation side edema from both sides Malori no young elastin young elastin production no young elastin

  17. Histologic verification: dynamics • PDT • = 405nm • D = 50J/cm2 in 1 day in 4 days in 7 days H & E edema from irradiation side edema from irradiation weak edema manifestation Mallory young elastin production excessive young elastin production production decrease

  18. Histologic verification: dynamics • PDT • =660nm • D = 50J/cm2 in 1 day in 4 days in 7 days H & E edema weak edema weak edema Mallory no young elastin production weak young elastin production weak young elastin production

  19. Histologic verification: dynamics • PDT • = 405nm • D = 150J/cm2 in 1 day in 4 days in 7 days Xi-65 staining for young endothelial cells

  20. Histology analysis of tissue reaction to PDT

  21. Temperature reaction to the procedure Temperature increase Absolute temperature M. Shakhova, et al, J. Biomed. Opt., in print (2018).

  22. Diagnostics and treatment of chronic pharyngitis • Chronic rhinitis is among the most frequent pathologies of ENT organs • Traditional diagnostic approaches provide low accuracy in differential diagnostics of chronic pharyngitis • Subjective evaluation of pharynx mucosa state by a clinician in pharyngoscopy may cause incorrect interpretation • Fast non-invasive diagnostic techniques are required • Correct choice of drug treatment requires knowledge the causative agent of the disease • OCT inspection in course of standard pharyngoscopy • PDT may produce wide-range antibacterial effect

  23. Visual inspection of pharynx in course of PDT treatment before in 1 day in 4 days in 7 days • chronic hyperemia • Palatine arches edema • pronounced vascular pattern • mucosa hypervascularization • decrease of inflammatory manifestations - activation of inflammatory processes (increase of local edema and hyperemia) • decrease of inflammatory manifestations • decrease of mucosa hypervascularization

  24. OCT monitoring of pharynx antimicrobial PDT before the second PDT procedure after PS administration after the first PDT procedure after the second PDT procedure before procedure 1 mm • photosensitizer: Revixan Derma, Russia • irradiation dose: 50 J/cm2 @ 405 nm • 24 hours between PDT procedures • PS acts as a clearing agent • Decrease in edema manifestation • Activation of lymph vessels and ducts

  25. Conclusions • Employment of two wavelengths provide additional optimization of the PDT procedure protocol • Equal light doses provide different effect at different wavelengths • Optical diagnostics techniques allow for non-invasive monitoring and evaluation of the procedure outcome • Monte Carlo OCT simulations allow to predict absorbed dose evaluation provides additional accuracy to adrenaline test results • Dual wavelengths fluorescence monitoring allows to evaluate both penetration and photobleaching of PS

  26. Team Clinicians M. Shakhova A. Meller D. Sapunov A. Shakhov N. Orlinskaya Physicists M. Kirillin E. Sergeeva D. Loginova A. Khilov V. Perekatova I. Turchin

  27. Acknowledgements Russian Science Foundation (project 17-15-01264) REVIXAN Ltd. Dr. Natalia Shakhova, MD, D.Sc., Prof.Institute of Applied Physics RAS, Russia Dr. Sergey Gamayunov, MD,Republican clinical oncologic dispensary, Chuvash Republic, Russia

  28. 2019 Nizhny Novgorod - Uglich - Nizhny Novgorod "Konstantin Korotkov" boat 3-7 August 2019 http://www.biophotonics.sci-nnov.ru/ Symposium ProgramOptical Bioimaging (Conference) Biophotonics in Cancer Research (Conference) Clinical Biophotonics (Workshop) Biophotonics in Stem Cells Research (Workshop) Symposium ChairsAmasiPeriasami, University of Virginia, USA Ilya Turchin, Institute of Applied Physics RAS, Russia Alfred Vogel, University of Luebeck, GermanyElena Zagaynova, Privolzhskiy Research Medical University, Russia

  29. Thank you for your attention! Questions?

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