Photodynamic therapy effect of m-THPC (Foscan®) in vivo: correlation with pharmacokinetics

Abstract

m-Tetra(hydroxyphenyl)chlorin (m-THPC, Foscan, Temoporfin) has an unusually high photodynamic efficacy which cannot be explained by its photochemical properties alone. In vivo interactions are therefore of critical importance in determining this high potency. The pharmacokinetics of m-THPC in a rat tumour model was determined using 14 C m-THPC in an LSBD 1 fibrosarcoma implanted into BDIX rats. The photodynamic therapy (PDT) efficacy was determined at different drug administrations to light intervals and correlated with the tumour and plasma pharmacokinetic data. The plasma pharmacokinetics of m-THPC can be interpreted by compartmental analysis as having three half-lives of 0.46, 6.91 and 82.5 h, with a small initial volume of distribution, suggesting retention in the vascular compartment. Tissues of the reticuloendothelial system showed high accumulation of m-THPC, particularly the liver. PDT efficacy of m-THPC over the same time course seemed to exhibit two peaks of activity (2 and 24 h), in terms of tumour growth delay with the peak at 24 h postinjection correlating to the maximum tumour concentration. Investigation on tumour cells isolated from m-THPC-treated tumours suggested that the peak PDT activity at 2 h represents an effect on the vasculature while the peak at 24 h shows a more direct response. These results indicate that the in vivo PDT effect of m-THPC occurs via several mechanisms. British Journal of Cancer (2003) Photodynamic therapy (PDT) is becoming accepted as an alternative to conventional cancer treatments for certain indications and other nononcological conditions. It is based on a tumour accumulation of a photosensitiser, which, when activated by light, results in tumour destruction via reactive oxygen species (Ochsner, 1997). The selectivity of PDT relies upon the targeting of the light delivery in combination with the accumulation/retention of the photosensitiser in malignant tissue. The time interval between photosensitiser administration and light delivery is crucial for the optimal clinical efficacy of PDT. The distribution of the photosensitiser both in the tumour as a whole and throughout the tumour compartments is dependent on this interval as well as in vivo interactions that affect photosensitiser aggregation, delivery and uptake (Boyle and Dolphin, 1996). m-Tetra (hydroxyphenyl)chlorin (m-THPC), a second-generation photosensitiser, has already been shown to be more potent than Photofrin (PII). It has been suggested that it is up to 200 times more powerful (Van Geel et al, 1995;Ball et al, 1999). This figure takes into account the drug dose required (0.15 mg kg À1 compared to 10 mg kg À1 for PII) and the lower light doses necessary (30 J cm À1 rather than 150 J cm À1 ) to produce similar PDT results. However, the reason for this effectiveness remains unresolved even considering the advantageous photoproperties of increased molar absorption coefficient and a favourable shift in the wavelength maximum (652 nm rather than 630 nm) (Bonnett et al, 1989).Preclinical studies have alread...

Enhanced photodynamic destruction of a transplantable fibrosarcoma using photochemical internalisation of gelonin

“…The initial rapid elimination phase, representing the distribution of the photosensitiser to the various organs was followed by a second phase representing drug elimination. The two half-lives are similar to those for the clearance of m-THPC (Cramers et al, 2003;Jones et al, 2003). At the start of the second phase (about 24 h after administration), the serum concentration is approximately 30-fold lower than in tumour tissue, so from this time onwards, there is unlikely to be a significant PDT effect on blood components under the conditions required for tumour necrosis.…”

Optimizing Photodynamic Therapy:In vivoPharmacokinetics of Liposomalmeta-(Tetrahydroxyphenyl)Chlorin in Feline Squamous Cell Carcinoma

“…This suggests that illumination in clinical PDT should be done at highest plasma levels, targeting the vasculature more than the tumor cell directly. In another study, m-THPC-PDT had two peaks of activity: an early effect on tumor vasculature synchronous to the plasma peak level followed by a late direct effect at maximum tumor accumulation (9). After having determined the tumor and tissue peaks in the feline species, our next step will be to compare the PDT outcome of the cats treated to date with cats treated optimally (i.e., at the time of highest liposomal m-THPC tumor accumulation versus cats treated at the time of the plasma peak).…”

“…A longer drug-light interval results in maximal concentration of the photosensitizer in the tumor, causing direct tumor cell destruction. This was shown recently for the secondgeneration photosensitizer meta-(tetrahydroxyphenyl)chlorin [m-THPC (Foscan)] and indicates that the in vivo effects occur via an indirect vascular effect as well as a more direct effect at different drug-light intervals (9,10).…”

Photodynamic Therapy in the Treatment of Osteomyelitis

“…A successful example was Foscan (Tetra-meso hydroxyphenyl chlorin, Figure 2F), which is a powerful intra-cellular photosensitizer. Its high photodynamic efficiency has been explained by the photooxidation of intracellular targets, because the quantum yields of singlet oxygen production is comparable or inferior to other relevant photosensitizers [36,37]. The intracellular generation of protoporphyrin IX by administration of its metabolic precursors (ALA), was another successful example that helped to expand the applications of PDT ( Figure 2E).…”