Photosensitizer agents
- Carole Thomas
- Stéphanie Lemaitre
- Mihaela Lupu
- Philippe Maillard
Photosensitizers for Retinoblastoma
The current treatment for retinoblastoma, the most frequent eye tumour in children, exposes the patient to the long-term consequences of chemotherapy. We are exploring an alternative non-mutagenic treatment using glycoconjugated photosensitizers targeting overexpressed lectins specific of this tumour (Fig. 3)
We have studied the photodynamic therapy applied as an antitumoral therapy followed-up non-invasively via sodium MRI.
Photodynamic therapy (PDT) uses a light activated, non-mutagenic photosensitiser dye (PS) from the phorphyrin family. Once systemic administered and light activated it may generate oxidative species that are responsible for the therapeutic effects, inducing thus cellular death via apoptosis and/or necrosis. Two treatment protocols were used, one targeted the tumor vascular system and the second targeted both vascular system and the tumoral cells. The difference between the two treatment protocols consists in the time lapse between the PS administration and the light activation. A short period of time (10 min) favours the ROSs initiation into the vascular system only while a longer period (3 h) favours the ROSs initiation inside cells. A double PS administration at different periods of time may target both vascular system and tumoral cells.
A typical example of longitudinal follow-up in the case of PDT treated human retinoblastoma grafted on nude mice.
Left : proton MRI, centre : sodium MRI, right : superposition of both imaging modalities. Before PDT, sodium imaging shows a poor sodium contrast due to the high cellular density of the tumor, and hence a relatively small extracellular volume rich in sodium.
Few hours after PDT a few mm, high contrast region appeared due to the cellular death induced by the generated ROSs inside cells. The extracellular compartment reach in sodium invaded the treated region. These first tumoral damages were induced on the light penetration pathway into the tissue (2-3 mm). 24 hours after PDT, all the tumor appears damaged as shown by high contrast sodium image all over the images slice. Since the generated ROSs have a very short lifetime the cellular death observed late after PDT is due to other biological mechanisms, like cellular death signals induced by the first layer of cells killed by PDT. This death mechanism, favoured by high cellular density architecture is known as bystander effect.
Getting closer to the clinical conditions we started studies on orthotopic xenograft mice model of retinoblastoma. After subretinal injection, retinal images and optical coherence tomography (OCT) were used to monitor tumor growth using the Micron IV (Phoenix Research Labs USA).
