Targeted Delivery of Paclitaxel to EphA2-Expressing Cancer Cells

Abstract

Purpose YSA is an EphA2-targeting peptide that effectively delivers anti-cancer agents to prostate cancer tumors (1). Here, we report on how we increased the drug-like properties of this delivery system. Experimental Design By introducing non-natural amino acids, we have designed two new EphA2 targeting peptides: YNH, where norleucine and homoserine replace the two methionine residues of YSA, and dYNH, where a D-tyrosine replaces the L-tyrosine at the first position of the YNH peptide. We describe the details of the synthesis of YNH and dYNH paclitaxel conjugates (YNH-PTX and dYNH-PTX) and their characterization in cells and in vivo. Results dYNH-PTX showed improved stability in mouse serum and significantly reduced tumor size in a prostate cancer xenograft model and also reduced tumor vasculature in a syngeneic orthotopic allograft mouse model of renal cancer compared to vehicle or paclitaxel treatments. Conclusion This study reveals that targeting EphA2 with dYNH drug conjugates could represent an effective way to deliver anti-cancer agents to a variety of tumor types. Translational Relevance Overexpression of the EphA2 positively correlates with tumor malignancy and poor prognosis. For this reason, EphA2 is an attractive target for cancer cell specific drug delivery. In this study, we report on the development of dYNH, an EphA2 targeting peptide that when coupled to paclitaxel (PTX) has favorable pharmacological properties and possesses powerful anti-tumor activity in vivo. dYNH-PTX may allow for an expanded therapeutic index of paclitaxel as well as precluding the need for complex formulations and long infusion times.

Combination Approach of YSA Peptide Anchored Docetaxel Stealth Liposomes with Oral Antifibrotic Agent for the Treatment of Lung Cancer

“…18,19 Recently, an ephrin mimicking amino acid sequence (YSA; YSAYPDSVPMMS) is a peptide identified to selectively target EphA2 receptor activation and cellular internalization. 20,21 …”

The Quest for an Effective Treatment for an Intractable Cancer

“…Both YNH and dYNH were complexed with paclitaxel (YNH-PTX and dYNH-PTX, respectively) and evaluated both in vitro and in vivo for activity in human prostate and mouse renal cancer cells. dYNH-PTX displayed enhanced stability versus YSA-PTX or YNH-PTX in mouse serum with enhanced antitumor and antivascular activity as compared with vehicle or paclitaxel treatments (Wang et al, 2013). Moreover, these proof-of-principle studies support the concept of structurally modifying the EphA2 ligand to develop drug conjugates with potential to treat a variety of cancer types that display elevated EphA2 expression.…”

“…Once the receptor is activated, the peptide and its attached drug are internalized into a lysosome, where the peptide is degraded and the drug is free to exert its toxic effects on the cell (Wang et al, 2012). Previous studies have shown that paclitaxel conjugated with these peptides shows increased efficacy in prostate and renal cancers (Wang et al, 2013).…”

“…In the modified YNH peptide, norleucine and homoserine replace the two methionine residues of YSA, and D-tyrosine replaces the L-tyrosine in the first position of the YNH peptide, resulting in dYNH (Wang et al, 2013). Both YNH and dYNH were complexed with paclitaxel (YNH-PTX and dYNH-PTX, respectively) and evaluated both in vitro and in vivo for activity in human prostate and mouse renal cancer cells.…”

Design and Modification of Anticancer Peptides

“…Hilchie et al [19] designed a analog of NRC-03 by replacing all the original amino acids with the corresponding D-amino acids, named [D]-NRC-03, which exhibited higher anticancer activity than NRC-03 due to the stability against human serum or trypsin [21]. Except D-amino acid, other unnatural amino acids also have been used to modify the anticancer peptide to increase their stability or bioactivity [22][23][24]. Anticancer peptide of…”