Sehgal Inder, Sibrian-Vazquez Martha, Vicente M Graça H
Department of Comparative Biomedical Sciences, Louisiana State University, Baton Rouge, Louisiana 70803, USA.
J Med Chem. 2008 Oct 9;51(19):6014-20. doi: 10.1021/jm800444c.
A series of five porphyrin-peptide conjugates bearing one or two sequences containing a cell penetrating peptide (CPP), a nuclear localization signal (NLS), or a bifunctional CPP-NLS or NLS-CPP sequences were synthesized and investigated in vitro using PC-3M human prostate cancer cells, in comparison with FDA-approved purified hematoporphyrin derivative (Porfimer Sodium) and mTHPC. The most promising porphyrin-HIV-1 Tat (48-60) conjugate 2 [lowest dark cytotoxicity (IC50 = 38.0 microM), highest phototoxicity (IC50 = 0.40 microM at 1 J/cm2)] was further evaluated in an in vivo biodistribution study using SCID mice bearing PC-3M tumors, in comparison with purified hematoporphyrin derivative. Porphyrin conjugate 2 was more tumor selective than the hematoporphyrin derivative and accumulated to a significantly greater extent in tumors. Our results show that effective photodynamic cytotoxicity can be induced in human prostate cancer cells with minimal dark toxicity and that selective accumulation in prostate tumors can be achieved in vivo with porphyrin-targeted photosensitizers.
合成了一系列含有一个或两个序列的卟啉-肽缀合物，这些序列包含细胞穿透肽（CPP）、核定位信号（NLS）或双功能CPP-NLS或NLS-CPP序列，并使用PC-3M人前列腺癌细胞进行体外研究，同时与FDA批准的纯化血卟啉衍生物（卟吩姆钠）和mTHPC进行比较。最有前景的卟啉-HIV-1 Tat（48-60）缀合物2 [最低暗细胞毒性（IC50 = 38.0 microM），最高光毒性（在1 J/cm2时IC50 = 0.40 microM）]，与纯化血卟啉衍生物相比，在携带PC-3M肿瘤的SCID小鼠体内生物分布研究中进一步评估。卟啉缀合物2比血卟啉衍生物具有更高的肿瘤选择性，并且在肿瘤中的积累程度明显更高。我们的结果表明，在人前列腺癌细胞中可以诱导有效的光动力细胞毒性，同时具有最小的暗毒性，并且使用卟啉靶向光敏剂可以在体内实现前列腺肿瘤的选择性积累。
