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Photodynamic Therapy

CZECH TECHNICAL UNIVERSITY IN PRAGUE FACULTY OF BIOMEDICAL ENGINEERING. Photodynamic Therapy. Martin Hof, Radek Macháň. Photodynamic Therapy (PDT). Origin of tumors and the principles of their treatment Principles and history of PDT Photo-physical and -chemical aspects

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Photodynamic Therapy

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  1. CZECH TECHNICAL UNIVERSITY IN PRAGUE FACULTY OF BIOMEDICAL ENGINEERING Photodynamic Therapy Martin Hof, Radek Macháň

  2. Photodynamic Therapy (PDT) • Origin of tumors and the principles of their treatment • Principles and history of PDT • Photo-physical and -chemical aspects • Photosensitizers (PS) of 1. generation • Endogenous photosensitizer • Photosensitizers of 2. and 3. generation • Summary

  3. Origin of tumors A A. Individual cells with modified genome B B. Hyperplasia:mutated cells are phenotypically identical with the healthy ones but they multiply faster C. Dysplasia: abnormalities in cell shape and orientation C

  4. Origin of tumors D D. Noninvasive carcinoma: The cells differ more in appearance and multiplication rate. The tumor does not spread to other tissues E E. Invasive carcinoma:Spreading out of the tissue of origin: individual cells are transported by cardiovascular and lymphatic system; a malignant tumor can lead to metastasis over the whole body

  5. Traditional Surgery Radiotherapy Chemotherapy New developments Boron neutron capture therapy Monoclonal antibody therapy Antigene or antisense therapy Photodynamic therapy (PDT) Principles of tumor treatment

  6. Principles of photodynamic therapy of tumors (PDT) • Photosensitizers (PS) are not toxic “at dark” • PS accumulate in tumors • Illumination of the tumor leads to a) Fluorescence:diagnosis of the tumor b) Killing of tumor cells (Apoptosis, Necrosis)- PDT

  7. History of photodynamic therapy of tumors • 1900Acridin exhibits photo-toxicity (Raab) • 1903 Eosin applied against skin cancer (von Tappeiner) • 1908Photo-toxicity of porphyrins (Hausmann) • 1913 Mayer-Betz tested photodynamic therapy with porphyrins on his skin • 1924 Porphyrin enriched tissue exhibits red fluorescence upon illumination with UV radiation (Policard) • 1942Different retention of porphyrins in helathy and malignant tissues (Auler, Banzer)

  8. History of photodynamic therapy of tumors • 1948Diagnosis and treatment of cancer by hematoporphyrin and its complexes with zinc (Figge) • 1961Lipson developed a hematoporphyrin derivative (HpD). • 1966first successful breast cancer treatment by HpD (Lipson) • 1978first systematic clinical studies (Dougherty) • Todaya few thousand patients treated by HpD • Photosensitizers of the first generation

  9. Photosensitizers of the first generation are oligomers (HpD) of Hematoporphyrin(Hp) • Absorption at 405, 505, 525, 565 and630 nm • Emission at635 and700 nm • Accumulation in tumors Dihemato-porphyrin- ether Hp

  10. Photophysics (Jablonski) Intersystem Crossing: kisc S1 Fluorescence: kf Energy of the states knrS Nonradiative transitions: knrT Phosphorescence: kp Quantum Yields: F: f = kf / (kf + knrS +kisc) ISC: isc = kisc / (kf + knrS +kisc) P:p = isc  kp / (kp + knrT) Excited state reactions of photosensitizer in T1 state represent an additional nonradiative decay pathway. Reaction with O2 gives rise to singlet oxygen1O2. Electron transfer reactions give rise to free radicals

  11. What is1O2? E • O2 is paramagnetic (in triplet state) in the ground state (according to Hund rule) • Because of spin restriction triplet oxygen 3O2participates only in non-selective radical reactions Electron configuration of 3O2 • Singlet oxygen 1O2 is very reactive and selective 95 KJ/mol 1269 nm 3O2 1O2

  12. REAKCE Volné radikály Photochemistry FREE RADICALS Type 1 reaction (electron transfer) + O2 S1 Energy of the states Reactive Oxygen Species (ROS): Superoxide ·O2- Hydroxyl rad. ·OH … k O2 Type 2 reaction (energy transfer)  (1O2) = isc  k [3O2 ] / (k [3O2] + kp + knrT)

  13. HpD accumulates preferentially in membranes Plasma membrane Affected sites Nuclear membrane Mitochondria outer membrane Endoplasmatic reticulum inner membrane Lysosomes

  14. Reactionsof 1O2and ROSwith biomolecules Peroxidation Cause oxidative damage, which can lead ultimately to cell death Addition on cycles Oxidation

  15. BEFORE AFTER BEFORE – The photodynamic diagnostics (PDD) of a tumor AFTER – The tumor tissue has been removed by PDT

  16. Pros and cons of the 1. generation of photosensitizers • Photophysics: high isc and  (1O2 ),but relatively short wavelength absorption with a low absorption coefficient • in vivo activity: low dark activity, high photodynamic activity,but relatively low selectivity of absorption in tumors

  17. An example of HpD-PDT INJECTION intravenous ACUMULATION IN TISSUE ELIMINATION FROM ACUMULATION IN TUMOR Healthy tissue Skin Serum TUMOR ILLUMANTION weeks APOPTOSIS NECROSIS

  18. Endogenous PS: Cells produce their own PS Pp IX ALA • Photosesitizer protoporphyrin IX (Pp IX) is an intermediate of heme synthesis • The physiological concentration of Pp IX is low because of a controlled expression of its precursor 5-aminolevulinic acid (ALA) COO- CH2 CH2 C O CH2 NH2 MITOCHONDRIA ALA-synthase • The expression of ALA is feedback controlled via heme concentration Ferrochelatase succinyl-CoA + glycine Heme

  19. Endogenous PS: Cells produce their own PS Pp IX ALA • Administration of exogenous ALA breaks the feedback control and results in accumulation of Pp IX COO- CH2 CH2 C O CH2 NH2 • Concentration of Pp IX is higher in cancer cells due to their higher metabolic activity and in some cases also due to decreased efficiency of ferrochelatase and increased efficiency of Pp IX synthesis from ALA MITOCHONDRIA ALA-synthase Ferrochelatase succinyl-CoA + glycine Heme

  20. Photosensitizers of 2. generation:- long wavelength absorption with large extinction coefficient- selective accumulation in tumor Naphtalocyanine: ex= 820 nm Phtalocyanine: maximalex = 740 nm Chlorin e6: ex = 750 nm Porphycen: ex= 710 nm

  21. Photosensitizers of 3. generation (selective acculmulation) Antibody • Monoclonal antibodies bind selectively to an antigen on cancer cells • The spacer is either cyclodextrin or Avidin-Biotin-system PS Spacer „Drug Targeting“

  22. Summary Limitations: Low penetration depth in tissue (ideal for skin cancer or with endoscopic illumination) Advantages: Low cost Relatively low side effects Goals: High selectivity for cancer cells Optimal illumination dose Type I reaction Free radicals Energy of states Singlet Oxygen Type II reaction REAKCE Triplet Oxygen

  23. Methodological outlook:Multiphoton excitation • High intensity of ps- or fs-lasers • Excitation by light of double or triple wavelength compared to single photon excitation • Light of longer wavelength penetrates deeper to the tissue Longwave excitation of a PS with shortwave absorption

  24. Acknowledgement The course was inspired by courses of: Prof. David M. Jameson, Ph.D. Prof. RNDr. Jaromír Plášek, Csc. Prof. William Reusch Financial support from the grant: FRVŠ 33/119970

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