HYDROPHOBIC ZN(II)-NAPHTHALOCYANINES AS PHOTODYNAMIC THERAPY AGENTS FOR LEWIS LUNG-CARCINOMA

Four Zn(II) 2,3-naphthalocyanines (unsubstituted ZnNc1, tetracetylamid o substituted ZnNc2, tetramino substituted ZnNc3 and tetramethoxy subs tituted ZnNc4) incorporated into unilamellar liposomes of dipalmitoylp hosphatidylcholine have been injected intra-peritoneally (i.p.) (0.25- 0.3 mg kg(-1)) to male C57/Black mice bearing a transplanted Lewis lun g carcinoma. The pharmacokinetic investigations show that three of the four studied ZnNcs, 1, 2 and 4, are good tumor-localizers in Lewis lu ng carcinoma. The highest concentration is detected after ZnNc1 admini stration. The lowest tumor concentration as well as the lowest phototh erapeutic effect were established with ZnNc3. In previous work it was shown that this ZnNc did not differ from the other three studied ZnNcs regarding the quantum yield of O-1(2)-formation and the photoinduced electron transfer. Obviously not only the good photochemical propertie s but also the tumor drug uptake can be an important factor of effecti ve PDT. The biodistribution investigations also show that 72 h after d rug injection, the skin concentration of the studied ZnNcs returns to the original base line. Indeed, we can expect that the skin photosensi tivity will last for no longer than three days after PDT. The establis hed higher drug concentration in the tumor rather than in the liver ti ssue (20 h after injection) shows again the tumor targeting selectivit y of the applied liposome-sensitiser delivered procedure. Evaluating t he PDT effect as reflected in the dynamics of the mean tumor diameter, we obtained unambiguous data on the potential capacity of ZnNcs 1,2,4 as PDT-photosensitisers. The data obtained from the assessment of the cytotoxic effect of PDT on the basis of the degree of induced necrosi s, gave an adequate characterization of the tumor tissue destruction. The results from the morphological analysis show the presence of direc t photocytotoxic changes of neoplastic cell targets ie. membrane, mito chondria and rough endoplasmic reticulum, as well as delayed damage in the endothelial cells. The lack of haemorrhagic necrosis suggests a d ifferent mechanism of photonecrosis in comparison with the mechanism o f photoinduced tumor necrosis after HpD photosensitization, where heav y haemorrhagic changes are observed. We consider that the observed dif ferent mechanism of tumor cell photodamage is not a unique property of the studied ZnNcs because similar changes have been observed from oth er authors after Zn-phthalocyanine photosensitization. We also suppose that the nature of the induced necrosis is different from that of the spontaneous one (untreated tumors), where there was no established en dothelial cell damage. In conclusion we consider that ZnNc 1, 2 and 4 can be effective sensitizers for PDT of cancer owing to their selectiv e targeting and slow clearance from tumor tissue, fast clearance from skin and pronounced phototherapeutic effect evaluated by a large numbe r of parameters.