AN IN-VIVO QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIP FOR A CONGENERIC SERIES OF PYROPHEOPHORBIDE DERIVATIVES AS PHOTOSENSITIZERS FOR PHOTODYNAMIC THERAPY

An in vivo quantitative structure-activity relationship (QSAR) study w as carried out on a congeneric series of pyropheophorbide photosensiti zers to identify structural features critical for their antitumor acti vity in photodynamic therapy (PDT). The structural elements evaluated in this study include the length and shape (alkyl, alkenyl, cyclic, an d secondary analogs) of the ether side chain. C3H mice, harboring the radiation-induced fibrosarcoma tumor model, were used to study three b iological response endpoints: tumor growth delay, tumor cell lethality , and vascular perfusion. All three endpoints revealed highly similar QSAR patterns that constituted a function of the alkyl ether chain len gth and drug lipophilicity, which is defined as the log of the octanol :water partition coefficient (log P). When the illumination of tumor, tumor cells, or cutaneous vasculature occurred 24 h after sensitizer a dministration, activities were minimal with analogs of log P less than or equal to 5, increased dramatically between log P of 5-6, and peake d between log P of 5.6-6.6. Activities declined gradually with higher log P. The lack of activity of the least-lipophilic analogs was explai ned in large part by their poor biodistribution characteristics, which yielded negligible tumor and plasma drug levels at the time of treatm ent with light. The progressively lower potencies of the most lipophil ic analogs cannot be explained through the overall tumor and plasma ph armacokinetics of photosensitizer because tumor and plasma concentrati ons progressively increased with lipophilicity. When compensated for d ifferences in tumor photosensitizer concentration, the 1-hexyl derivat ive (optimal lipophilicity) was 5-fold more potent than the 1-dodecyl derivative (more lipophilic) and 3-fold more potent than the 1-pentyl analog (less lipophilic), indicating that, in addition to the overall tumor pharmacokinetics, pharmacodynamic factors may influence PDT acti vity. Drug lipophilicity was highly predictive for photodynamic activi ty. QSAR modeling revealed that direct antitumor effects and vascular PDT effects may be governed by common mechanisms, and that the mere as sociation of high levels of photosensitizer in the tumor tissue is not sufficient for optimal PDT efficiency.