Photodynamic Therapy (PDT) Marek Scholz BEFORE AFTER

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“

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

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 ...

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.

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

Principle of tumor erradication by PDT

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

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

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

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.

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 ...

New concepts and trends in PDT Photosensitizers of 3. generation

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

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

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