Design and synthesis of a tripartate paclitaxel prodrug for melanoma therapy.

Therapy of melanoma continues to be a challenge since, regardless of the treatment used, long-term survival is quite uncommon. In an attempt to improve the effectiveness and decrease the toxicity of anticancer chemotherapy, one useful approach might be to administer a prodrug that specifically releases the active cytotoxic drug at the tumor site. In this work, we describe the synthesis of a peptide conjugate of paclitaxel potentially useful in the treatment of human melanoma, and characterized by the simultaneous presence of three functional domains: a “targeting domain”, an “activation sequence”, and the antitumor drug paclitaxel. The “targeting domain” of the prodrug is represented by an RGD-containing cyclic peptide, able to bind selectively to alpha-V beta-3 integrin, which is known to be highly over-expressed by both metastatic human melanoma cells, and endothelial cells of tumor vessels. The “activation sequence”, responsible for the selective release of the drug, is a short peptide which is cleaved specifically by cathepsin B, a protease highly up-regulated in malignant tumors. The results of NMR conformational studies, as well as those of biological experiments aimed at evaluating the plasma stability of the prodrug and its ability to inhibit alpha-V beta-3–mediated tumor cell adhesion to vitronectin, are presented.