Design and synthesis of paclitaxel conjugated with an ErbB2‐recognizing peptide, EC‐1

Abstract

The selective delivery of therapeutic agents to receptors overexpressed in cancer cells without harming the rest of the body is a major challenge in clinical oncology today. In this study, we report the design and synthesis of paclitaxel (PTX) conjugated with an erbB2-recognizing peptide (EC-1). The cyclic peptide EC-1 specifically binds to the extracellular domain of ErbB2 and selectively inhibits proliferation of breast cancer cells overexpressing ErbB2. PTX is a potent antitumor agent commonly used in the treatment of advanced metastatic breast cancer, yet patients have to suffer some side effects caused by its systemic toxicity. The aim of our conjugate is to specifically deliver antitumor agent PTX to breast cancer cells that overexpress oncogenic ErbB2 with the purpose to reduce toxicity and enhance selective killing of cancer cells. In this study, a concise and efficient synthetic route for the preparation of the PTX-EC-1 conjugate has been developed in 6% overall yield. This synthetic approach provides a general method for conjugating a highly functionalized and disulfide-bridge containing cyclopeptide to Taxol or other antitumor agents.

Biological evaluation of Paclitaxel-peptide conjugates as a model for MMP2-targeted drug delivery

“…For example, ErbB2 has been used for targeting taxane to breast cancer. 27 Also, the taxanes can be conjugated with monoclonal antibodies (mAbs) against tumor cell surface markers. One example is cBR96doxorubicin, which is selectively internalized and activated by a wide variety of human carcinomas expressing an extended form of Lewis Y antigen [Le(y)].…”

Chemical modulation of bioactive compounds via oligopeptide or amino acid conjugation

“…ErbB2-recognizing peptide, EC-1, was conjugated with an anticancer drug, paclitaxel, to selectively inhibit the proliferation of breast cancer cells over-expressing ErbB2. 26 Loh et al 27 recently reported an approach using localizing peptide conjugates to transport small molecule inhibitors to the subcellular compartment of cells where a target enzyme can be found. Cathepsins are cysteine proteases that mostly exist in endolysosomal vesicles.…”

“…Daunomycin‐LTVSPWY conjugates were highly cytostatic and taken up efficiently by human cancer cells. ErbB2‐recognizing peptide, EC‐1, was conjugated with an anticancer drug, paclitaxel, to selectively inhibit the proliferation of breast cancer cells over‐expressing ErbB2 …”

Medicinal Chemistry of α‐Hydroxy‐β‐Amino Acids

“…Two copies of the cyclic peptide targeting receptor were conjugated to paclitaxel in the same manner as in the approach above and showed preferential cytotoxicity to integrin-expressing tumor cells. Several other prodrugs targeting somatostatin receptor [293], ErbB2 (receptor tyrosine kinases) [294], folate receptor [295], and luteinizing hormonereleasing hormone have been synthesized [296]. Receptors can be also targeted by monoclonal antibodies.…”