Targeted delivery of paclitaxel to tumor cells: synthesis and in vitro evaluation

We previously reported a novel drug delivery system, drug-linker-Phe-Phe-Arg-methylketone-(FFR-mk)-factor VIIa (fVIIa). The method utilizes tissue factor (TF), which is aberrantly and abundantly expressed on many cancer cells. The advantage of this delivery system is its ability to furnish a potent anti-cancer drug specifically to the tumor vasculature and cancer cells. In this paper, we describe the synthesis of paclitaxel (PTX)-Phe-Phe-Arg-chloromethyl ketone (FFR-ck), followed by coupling with fVIIa to form PTX-FFR-mk-fVIIa. FFRck was separately linked to the OH groups at the C2′ or C7 positions of PTX (C2′- or C7-PTX-FFRck), the C2′ analog exhibiting better activity against human head and neck squamous KB 3-1 cells. The activity order against PTX-sensitive KB 3-1 cells is C2′-PTX-FFRmk-fVIIa > PTX >C2′-PTX-FFRck. The C2′-complex shows an IC50 of 12 nM against the PTX-sensitive cell line and 130 nM against PTX-resistant cells. a