Biodistribution and bioactivity of tetra-pegylated meta-tetra(hydroxyphenyl)chlorin compared to native meta-tetra(hydroxyphenyl)chlorin in a rat liver tumor model

It has been proposed that the construction of a photosensitizer-polymer con jugate would lead to an increased selective retention of the drug in tumor tissue resulting in an enhancement of selective turner destruction by light in photodynamic therapy. In this study the kinetics of a tetrapegylated de rivative of meta-tetra(hydroxyphenyl)chlorin (mTHPC-PEG) were compared with those of native meta-tetra(hydroxyphenyl)chlorin (mTHPC) in a rat liver tu mor model. In addition, the time course of bioactivity of both drugs was st udied in normal liver tissue. Pegylation of mTHPC resulted in a two-fold in crease in the plasma half-life time, a five-fold decrease in Liver uptake a nd an increase in the tumor selectivity at early time intervals after drug administration, However, although mTHPC concentrations in liver decrease ra pidly with time, mTHPC-PEG liver concentrations increased as a function of time. This led to a loss of tumor selectivity at all but the earliest time points, whereas with mTHPC tumor selectivity increased with time. For both drugs the time course of bioactivity in the liver parallels drug concentrat ion levels with extensive necrosis after irradiation of mTHPC-PEG-sensitize d liver tissue up to drug-light intervals of 120 h, It is concluded that on balance mTHPC-PEG does not appear to show any benefits over native mTHPC f or the treatment of liver tumors, as normal liver tissue accumulates the co mpound. However, pegylation is a potentially promising strategy,vith an inc rease in tumor selectivity and reduced liver uptake if accumulation in the liver can be prevented.