Targeting delivery of paclitaxel into tumor cells via somatostatin receptor endocytosis

Background: The binding of somatostatin (SST) to endogenous G-protein-coupl ed receptors (SST receptors or SSTRs) is followed by internalization of SST , and, several reports have shown that a high density of SSTRs is present o n most hormone-secreting tissue tumors. Facile synthesis of the long-acting SST analog, octreotide, has previously been described. Octreotide might be of practical value in developing tumor tracers and in serving as a carrier of cytotoxic antitumor drugs. Results: Fluorescein-labeled octreotide was internalized into the cytosol o f human breast MCF-7 carcinoma cells via binding to SSTRs. Octreotide-conju gated paclitaxel (taxol) was created by coupling taxol-succinate to the ami no-terminal end of octreotide. This conjugate retains the biological activi ty of taxol in inducing formation of tubulin bundles, eventually causing ap optosis of MCF-7 cells. Cytotoxicity of octreotide-conjugated taxol is main ly mediated by SSTR, as shown by the observation that octreotide pretreatme nt can rescue the induced cell death. In comparison with free taxol, this c onjugate shows much less toxicity in Chinese hamster ovary cells. Conclusions: Octreotide-conjugated taxol exerts the same antitumor effect o f free taxol on stabilizing microtubule formation and inducing cell death. This conjugate triggers tumor cell apoptosis mediated by SSTRs and is exclu sively toxic to SSTR-expressing cells. Octreotide-conjugated taxol is less toxic to low-SSTR-expressing cells compared with free taxol. Our results st rongly indicated that octreotide-conjugated taxol demonstrates cell selecti vity and may be used as a targeting agent for cancer therapy.