Foscan® uptake and tissue distribution in relation to photodynamic efficacy

Abstract

Clinical photodynamic therapy (PDT) schedules are based on the assumption that optimum drug -light intervals are times at which there is a maximum differential between photosensitiser retention in the tumour and surrounding normal tissue. However, vascularmediated effects contribute to tumour destruction by PDT; therefore, plasma sensitiser levels and endothelial cell drug exposure could also be important determinants of PDT response. The purpose of this study was to investigate the influence of tumour, tissue and plasma concentrations of the photosensitiser Foscan s (meta-tetrahydroxyphenylchlorin, mTHPC) on PDT response. Groups of BalbC nude mice, bearing human mesothelioma xenografts (H-MESO1) were injected (i.v.) with a single dose of 14 C-labelled mTHPC, or with two doses, separated by 72 h. Drug levels in plasma, tumour and normal tissues were measured at 5 min to 120 h after drug administration. The PDT tumour and skin responses were evaluated by illuminating separate groups mice at intervals of 5 min to 120 h after injection of Foscan (nonlabelled). Drug levels in both tumour and skin increased during the first 24 h after a single injection, and remained almost constant for at least 120 h. The second injection produced a further, rapid increase in mTHPC levels in tumours and skin, with steady state being maintained from 20 min to 120 h. By contrast, PDT response of both tumours and skin were maximal for illumination at 1 -3 h after drug, with very little response when illumination was given 48 -120 h after drug. There was no significant correlation between tumour or skin drug level and PDT response. There was, however, a significant correlation between plasma drug levels and tumour or skin response, excluding an initial distribution time of 20 min. These studies demonstrate a pronounced disassociation between tumour drug levels and optimum drug -light intervals for PDT response with Foscan. We suggest that the PDT effect, in both tumours and normal tissues, is largely mediated via vascular damage and that the selectivity of PDT is not based on differential tumour drug uptake.

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

“…There is also a high initial retention in the vasculature that is confirmed by initial volume of the distribution (32.0 ml kg À1 ), which is small compared to the blood volume of a rat (50 -70 ml kg À1 ). m-Tetra (hydrophenyl)chlorin may be initially retained in the vascular system, possibly due to protein binding or precipitation (Clark and Smith, 1986). This is consistent with plasma binding studies with m-THPC that shows an unusual initial protein-binding pattern for a hydrophobic photosensitiser (Hopkinson et al, 1999).…”

“…The plasma levels were initially high (9.37 mg ml À1 ) and appear to declined exponentially as would normally be expected for an intravenous injection. The clearance from plasma, however, did not follow a simple monoexponential decay but could be fitted to multiple exponentials, and because of this the data were analysed by both a noncompartmental and a compartmental approach (Yamaoko et al, 1978;Clark and Smith, 1986). With a compartmental approach, the data best fit a three exponential decay described by the equation C ¼ 5.89 e À1.51t þ 3.36 e À0.1t þ 0.120 e À0.0084t .…”

“…for all three animals at each time point were calculated. The plasma pharmacokinetics was analysed by compartmental and noncompartmental mathematical methods (Yamaoka et al, 1978;Clark and Smith, 1986).…”

Photodynamic Therapy in Oncology

“…However, recent animal studies [8,9] and clinical data [10] have shown that the concentration of sensitizer in the tumor at the time of illumination does not necessarily predict response to PDT. Plasma concentration at the time of illumination is a better indicator for PDT outcome [11][12][13][14]. This suggests that tumor cells may not always be direct targets of PDT, but they may be indirectly killed as a result of damage to other cell types, for example, vascular endothelial cells.…”

“…Furthermore, inhibition of inflammatory responses and vasoconstriction decrease tumor response to PDT, whereas concomitant pharmacological inhibition of angiogenesis enhances the PDT response [11][12][13][14][20][21][22][23][24]. All these studies demonstrate the importance of vascular-mediated damage in obtaining an effective tumoricidal effect after in vivo PDT.…”