1. Photodynamic Therapy (PDT)
Marek Scholz
BEFORE
AFTER

2. Brief history of phototherapy and photodynamic therapy
Ancient Greek, Egypt, China: „heliotherapy“ for vitiligo, psoriarsis, rickets
re-discovered in 19th century: rickets (vitamin D deficiency)
1903: Niels Finsen - Nobel price for treatment of lupus vulgaris with arc-lamp
Photochemotherapy
1900: Raab&Tappenier – investigating toxicity of various dyes towards protozoa Noticed that the toxicity of acridine depends on the time of the day light required!. Hypothesis: fluorescent materials as therapeutic agents
1904: Tappenier&Jesionek – toxic effect depends on the presence of oxygen. Treatment of skin cancer and lupus with eosin.
1907: Coined the term Photodyamic Therapy for „oxygen-dependent photosensitization“

3. brief history continued
1908: dyes isolated from blood – hematoporphyrin – kill paramecia upon light exposure
1913: Meyer-Betz injected himself hematoporphyrin
1924: Policard – discovered spontaneous fluorescence of experimental tumors exposed to Wood lamp – attributed to porphyrins -> selective accumulation of porphyrins in tumors -> diagnostic purposes?
1942: Auler&Bansen: investigate selective accumulation of porphyrins in tumors, and they notice that the fluorescing tumors are more necrotic when exposed to light
1955: Schwartz attempts to find, isolate, and purify the most efficient component of hematoporphyrin mixture. Accidently synthesized a very potent hematoporphyrin derivative (HpD)
>1966 HpD used for breast cancer, bladder cancer
1978: Dougherty – first systematic trials
> 1980: more purified version of HpD Photofrin coming to market, development of new more potent photosensitizers (Tookas, Visudyne, ALA, ...)
dye (photosensitizer) + light + oxygen  cytotoxicity
porphyrins selectively accumulate in tumors

4. cancer treatment
Brainstorming – what are the differences between normal and cancerous cells?
rapid replication, impaired DNA repair, chromosome instability, lack of contact inhibition, dependent on expression of oncogenes, neoangiogenesis,...
Traditional cancer treatments:
surgery, chemotherapy, radiotherapy
What are the drawbacks of these therapies?
new treatments:
immunotherapy/biological therapy
proton therapy
photodynamic therapy
...

5. Principles of PDT – what kills the tumor?
Singlet oxygen (1O2), the first excited state of molecular oxygen, is an extremely strong oxidant and readily oxidizes a range of biomolecules (lipids, proteins, ...). The ground state of oxygen is a spin triplet (3O2) and because of the spin restriction it participates only in non-selective radical reactions.

6. Singlet oxygen
typical reactions of 1O2:
ground state
3O2

7. Principle of tumor erradication by PDT

8. Photochemistry
Formation of free radicals (HO•,O2-•)

9. Photosensitizers absorption spectra
More absorption in red = better. Why?

10. Light penetration into tissue
Therapeutic window for PDT ~ 650 – 1000 nm

11. Various photosensitizers
source:
O’Connor et al.: Porphyrin and Nonporphyrin Photosensitizers in Oncology: Preclinical and Clinical Advances in Photodynamic Therapy, PHOTOCHEMISTRY AND PHOTOBIOLOGY, 85 , 1053–1074, 2009.

12. Brainstorming: What properties a good photosensitizer should have?
high yield of singlet oxygen
strong absorption in red/NIR
selective accumulation in tumor tissue
low dark toxicity
convenient pharmacokinetics
convenient subcellular localization (mitochondria, ER, lysosomes)
still some fluorescence remaining that can be used for tumor imaging
manufacturability, high purity
...

13. New concepts and trends in PDT
Photosensitizers of 3. generation

14. Practical PDT - examples
ALA based PDT
photodiagnosis
Macular degeneration treatment – destruction of neovasculariazation by PDT

15. Practical PDT – examples
skin cancer treatment
Bringing light deep inside by light guides/optical fibers.

16. pros and cons of PDT Pros: + spatial and temporal control
+ non-toxic without light
+ immune response
+ less invasive than surgery
+ allows for fluorescence imaging, which can guide resection
+ low cost, quick, can be treated many times
precise targeting, low side-effects
cons (to be improved):
low depth of penetration
hypoxia problem
post-treatment skin photosensitivity