Karagianis G, Hill J S, Stylli S S, Kaye A H, Varadaxis N J, Reiss J A, Phillips D R
Department of Chemistry, La Trobe University, Bundoora, Victoria, Australia.
Br J Cancer. 1996 Feb;73(4):514-21. doi: 10.1038/bjc.1996.89.
A series of monomeric porphyrins (2-8) based on porphyrin C (1) have been tested as sensitisers for photodynamic therapy (PDT) of cerebral glioma using the in vitro/in vivo C6 intracerebral animal tumour model. The in vivo screening, consisting of cytotoxicity, phototoxicity (red light) and subcellular localisation studies, revealed two sensitisers (porphyrin 7, molecular weight 863 Da and porphyrin 8, molecular weight 889 Da), which had greater photoactivity than porphyrin C and similar photoactivity to haematoporphyrin derivative (HpD) although at a 5-fold higher dose than HpD. Both sensitisers showed intracellular localisation to discrete organelle sites and exhibited considerably less 'dark' cytotoxicity than HpD. The kinetics of uptake of porphyrins 7 and 8 was studied in the mouse C6 glioma model as well as in biopsy samples from normal brain, liver, spleen and blood. Maximal drug uptake levels in tumour occurred 9 and 6 h after intraperitoneal injection for 7 and 8 respectively, at which time the tumour to normal brain ratios were 15:1 and 13:1 respectively. The effect of PDT using porphyrin 7 activated by the gold metal vapour laser tuned to 627.8 nm was studied in Wistar rats bearing intracerebral C6 glioma. At a drug dose of 10 mg porphyrin 7 kg-1 body weight and laser doses of up to 400 J cm-2 light, selective tumour kill with sparing of normal brain was achieved, with a maximal depth of tumour kill of 1.77+/-0.40. mm. Irradiation following a higher drug dose of 75 mg porphyrin 7 kg-1 body weight resulted in a greater depth of tumour kill, but also significantly increased the likelihood and extent of necrosis in normal brain.
基于卟啉C（1）的一系列单体卟啉（2 - 8）已被用作脑胶质瘤光动力疗法（PDT）的敏化剂，采用体外/体内C6脑内动物肿瘤模型进行测试。体内筛选包括细胞毒性、光毒性（红光）和亚细胞定位研究，结果显示两种敏化剂（卟啉7，分子量863 Da和卟啉8，分子量889 Da），其光活性比卟啉C更高，且与血卟啉衍生物（HpD）的光活性相似，尽管剂量比HpD高5倍。两种敏化剂均显示在细胞内定位于离散的细胞器部位，并且与HpD相比，“暗”细胞毒性明显更低。在小鼠C6胶质瘤模型以及来自正常脑、肝、脾和血液的活检样本中研究了卟啉7和8的摄取动力学。腹腔注射后，卟啉7和8分别在9小时和6小时达到肿瘤内最大药物摄取水平，此时肿瘤与正常脑的比率分别为15:1和13:1。在携带脑内C6胶质瘤的Wistar大鼠中研究了使用调谐至627.8 nm的金金属蒸气激光激活卟啉7进行PDT的效果。在药物剂量为10 mg卟啉7 kg-1体重且激光剂量高达400 J cm-2光的情况下，实现了对肿瘤的选择性杀伤，同时正常脑得以保留，最大肿瘤杀伤深度为1.77±0.40 mm。在更高药物剂量75 mg卟啉7 kg-1体重后进行照射，导致更大的肿瘤杀伤深度，但也显著增加了正常脑坏死的可能性和程度。
