Mansour Ahmed M, Drevs Joachim, Esser Norbert, Hamada Farid M, Badary Osama A, Unger Clemens, Fichtner Iduna, Kratz Felix
Tumor Biology Center, Breisacher Strasse 117, 79106 Freiburg, Germany.
Cancer Res. 2003 Jul 15;63(14):4062-6.
The progression of malignant melanoma is characterized by overexpression of a number of matrix metalloproteinases (MMPs), especially MMP-2, which play a critical role in the degradation of basement membranes and the extracellular matrix. Consequently, we assessed a drug targeting strategy in which the protease activity of MMP-2 is exploited to release an anticancer agent from a macromolecular carrier, i.e., circulating albumin. For this purpose, a water-soluble maleimide derivative of doxorubicin (1) incorporating a MMP-2 specific peptide sequence (Gly-Pro-Leu-Gly-Ile-Ala-Gly-Gln) was developed that binds rapidly and selectively to the cysteine-34 position of circulating albumin. The albumin-bound form of 1 was efficiently and specifically cleaved by MMP-2 liberating a doxorubicin tetrapeptide (Ile-Ala-Gly-Gln-DOXO) and subsequently doxorubicin. In vivo, 1 was superior to the parent compound doxorubicin in the A375 human melanoma xenograft, which is characterized by a high expression of MMP-2.
恶性黑色素瘤的进展特征是多种基质金属蛋白酶（MMPs）的过表达，尤其是MMP-2，其在基底膜和细胞外基质的降解中起关键作用。因此，我们评估了一种药物靶向策略，即利用MMP-2的蛋白酶活性从大分子载体（即循环白蛋白）释放抗癌剂。为此，开发了一种阿霉素的水溶性马来酰亚胺衍生物（1），其包含MMP-2特异性肽序列（Gly-Pro-Leu-Gly-Ile-Ala-Gly-Gln），该衍生物能快速且选择性地与循环白蛋白的半胱氨酸-34位点结合。1与白蛋白结合的形式被MMP-2有效且特异性地切割，释放出阿霉素四肽（Ile-Ala-Gly-Gln-DOXO），随后释放出阿霉素。在体内，在以高表达MMP-2为特征的A375人黑色素瘤异种移植模型中，1优于母体化合物阿霉素。
