Effect of chemical structure and hydrophobicity on the pharmacokinetic properties of porphycenes in tumour-bearing mice

The efficiency and selectivity of tumour targeting by several tetra-n-propylporphycene (TPPn) and tetrakis(methoxyethyl)porphycene (TMPn) derivatives have been studied by administering 3.76 micromol/kg of aqueous or liposomal porphycene formulations to BALB/c mice bearing an i.m. implanted MS-2 fibrosarcoma. These 2 parameters have been studied as a function of the type of substituents linked to the 9-position of the macrocycle by amide, ester or ether functional groups. The pharmacokinetic properties appear to be controlled mainly by the degree of porphycene hydrophobicity, as evaluated by measuring their retention times in a C 18 column for HPLC. Thus, the post-injection time (T50) at which the porphycene concentration in the plasma decreases to 50% of the initial value ranged from a few minutes for the less hydrophobic to several hours for the more hydrophobic porphycenes. An increase in hydrophobicity also was accompanied by an enhanced efficiency and selectivity of tumour targeting. The less hydrophobic porphycenes showed a maximum tumour uptake of 0.5-2 nmol/g of tissue at 10-20 min after administration with a tumour/peri-tumoural concentration ratio around 2-3, while those with higher hydrophobicity reached tumour concentrations of 7-8 nmol/g at 24-48 hr after administration with concentration ratios higher than 20.